G2Cdb::Human Disease report

Disease id
D00000155
Name
Pelizaeus-Merzbacher disease
Nervous system disease
yes

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001806 PLP1
proteolipid protein 1
Y (1376553) Polymorphism (P) ?
G00001806 PLP1
proteolipid protein 1
Y (1376966) Unknown (?) Y
G00001806 PLP1
proteolipid protein 1
Y (1720927) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (2480601) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (7509234) Insertion (I) Y
G00001806 PLP1
proteolipid protein 1
Y (7509235) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (7539211) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (7539212) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (7539213) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (7541731) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (7573159) Microinsertion (MI) Y
G00001806 PLP1
proteolipid protein 1
Y (7679906) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (7684886) Microinsertion (MI) Y
G00001806 PLP1
proteolipid protein 1
Y (7684945) Frameshift mutation (FS) Y
G00001806 PLP1
proteolipid protein 1
Y (8786077) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (9008538) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (9056547) Nonsense (No) Y
G00001806 PLP1
proteolipid protein 1
Y (9106132) Unknown (?) Y
G00001806 PLP1
proteolipid protein 1
Y (9268109) Nonsense (No) Y
G00001806 PLP1
proteolipid protein 1
Y (9633722) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (9934976) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (10401787) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (10425042) Single nucleotide polymorphism (SNP) Y
G00001806 PLP1
proteolipid protein 1
Y (10588103) Microinsertion (MI) Y
G00001806 PLP1
proteolipid protein 1
Y (10588103) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (10827108) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (11071483) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (11139261) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (11180600) Unknown (?) Y
G00001806 PLP1
proteolipid protein 1
Y (11536268) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (11786921) Microinsertion (MI) Y
G00001806 PLP1
proteolipid protein 1
Y (11787038) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (12601703) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (12605435) Insertion (I) Y
G00001806 PLP1
proteolipid protein 1
Y (12605435) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (12891682) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (14533091) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (15689360) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (15712223) Microinsertion (MI) Y
G00001806 PLP1
proteolipid protein 1
Y (15712223) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (15712223) Deletion (D) Y
G00001806 PLP1
proteolipid protein 1
Y (15837131) Single nucleotide polymorphism (SNP) Y
G00001806 PLP1
proteolipid protein 1
Y (16380909) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (16416265) Duplication (Du) Y
G00001806 PLP1
proteolipid protein 1
Y (16416265) Deletion (D) Y

References

  • PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1.

    Combes P, Bonnet-Dupeyron MN, Gauthier-Barichard F, Schiffmann R, Bertini E, Rodriguez D, Armour JA, Boespflug-Tanguy O and Vaurs-Barrière C

    INSERM U 384, Faculté de Médecine, Place Henri Dunant, 63000 Clermont-Ferrand, France.

    The proteolipid protein 1 (PLP1) gene is known to be mutated in the X-linked disorders of myelin formation Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2. The most commonly found PLP1 mutations are gene duplications (60-70%) and point mutations (20%). About 20% of patients with a PMD phenotype do not present identified PLP1 mutation, thus suggesting genetic heterogeneity and/or undetected PLP1 abnormalities. Except the recently described MLPA screening the seven exonic regions, the currently used techniques to quantify PLP1 gene copy number do not investigate small intragenic PLP1 rearrangements. Using the multiplex amplifiable probe hybridization (MAPH) technique, we looked simultaneously for intragenic rearrangements along the PLP1 gene (exonic and regulatory regions) and for rearrangements in the GPM6B candidate gene (a member of the proteolipid protein family). We tested 262 hypomyelinating patients: 56 PLP1 duplicated patients, 1 PLP1 triplicated patient, and 205 patients presenting a leukodystrophy of undetermined origin with brain MRI suggesting a defect in myelin formation. Our results show that MAPH is an alternative reliable technique for diagnosis of PLP1 gene copy number. It allows us (1) to demonstrate that all PLP1 duplications previously found encompass the whole gene, (2) to establish that copy number changes in GPM6B and intragenic duplications of PLP1 are very unlikely to be involved in the etiology of UHL, and (3) to identify one partial triplication and two partial deletions of PLP1 in patients presenting with a PMD phenotype.

    Neurogenetics 2006;7;1;31-7

  • Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination.

    Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, Howell G, Gribble SM, Burford DC, Carter NP, Hobson DL, Garbern JY, Kamholz J, Heng H, Hodes ME, Malcolm S and Hobson GM

    Clinical and Molecular Genetics, Institute of Child Health, London.

    We describe genomic structures of 59 X-chromosome segmental duplications that include the proteolipid protein 1 gene (PLP1) in patients with Pelizaeus-Merzbacher disease. We provide the first report of 13 junction sequences, which gives insight into underlying mechanisms. Although proximal breakpoints were highly variable, distal breakpoints tended to cluster around low-copy repeats (LCRs) (50% of distal breakpoints), and each duplication event appeared to be unique (100 kb to 4.6 Mb in size). Sequence analysis of the junctions revealed no large homologous regions between proximal and distal breakpoints. Most junctions had microhomology of 1-6 bases, and one had a 2-base insertion. Boundaries between single-copy and duplicated DNA were identical to the reference genomic sequence in all patients investigated. Taken together, these data suggest that the tandem duplications are formed by a coupled homologous and nonhomologous recombination mechanism. We suggest repair of a double-stranded break (DSB) by one-sided homologous strand invasion of a sister chromatid, followed by DNA synthesis and nonhomologous end joining with the other end of the break. This is in contrast to other genomic disorders that have recurrent rearrangements formed by nonallelic homologous recombination between LCRs. Interspersed repetitive elements (Alu elements, long interspersed nuclear elements, and long terminal repeats) were found at 18 of the 26 breakpoint sequences studied. No specific motif that may predispose to DSBs was revealed, but single or alternating tracts of purines and pyrimidines that may cause secondary structures were common. Analysis of the 2-Mb region susceptible to duplications identified proximal-specific repeats and distal LCRs in addition to the previously reported ones, suggesting that the unique genomic architecture may have a role in nonrecurrent rearrangements by promoting instability.

    Funded by: NCRR NIH HHS: P20 RR-020173-01, P20 RR020173; NINDS NIH HHS: NS043783, R01 NS043783; Wellcome Trust

    American journal of human genetics 2005;77;6;966-87

  • Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease.

    Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, Palmer R, Stubbs P, Davies S, Endziniene M, Wu Y, Chong WK, Malcolm S, Surtees R, Garbern JY and Woodward KJ

    Clinical and Molecular Genetics, Institute of Child Health, London, UK.

    We describe five boys from different families with an atypically severe form of Pelizaeus-Merzbacher disease (PMD) who have three, and in one case, five copies of the proteolipid protein (PLP1) gene. This is the first report of more than two copies of PLP1 in PMD patients and clearly demonstrates that severe clinical symptoms are associated with increased PLP1 gene dosage. Previously, duplications, deletions and mutations of the PLP1 gene were reported to give rise to this X-linked disorder. Patients with PLP1 duplication are usually classified as having either classical or transitional PMD rather than the more rare severe connatal form. The clinical symptoms of the five patients in this study included lack of stable head control and severe mental retardation, with three having severe paroxysmal disorder and two dying before the first year of life. Gene dosage was determined using interphase FISH (fluorescence in situ hybridization) and the novel approach of multiple ligation probe amplification (MLPA). We found FISH unreliable for dosage detection above the level of a duplication and MLPA to be more accurate in determination of specific copy number. Our finding that three or more copies of the gene give rise to a more severe phenotype is in agreement with observations in transgenic mice where severity of disease increased with Plp1 gene dosage and level of overexpression. The patient with five copies of PLP1 was not more affected than those with a triplication, suggesting that there is possibly a limit to the level of severity or that other genetic factors influence the phenotype. It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection.

    Brain : a journal of neurology 2005;128;Pt 4;743-51

  • Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease.

    Hübner CA, Orth U, Senning A, Steglich C, Kohlschütter A, Korinthenberg R and Gal A

    Institute of Human Genetics, University Hospital Eppendorf, Hamburg, Germany. c.huebner@uke.uni-hamburg.de

    Pelizaeus-Merzbacher disease (PMD) is a rare X-chromosomal neurodegenerative disorder that affects primarily the white matter of the central nervous system and is caused by mutations of the PLP1 (proteolipid protein 1) gene. We performed mutation analysis of 133 male patients with suspected PMD. Following SSCP analysis of all coding exons of PLP1, we found most likely pathogenic mutations (single base substitutions and small rearrangements) including 17 novel sequence variants in 21 (15.8%) patients. Most patients with missense mutations had a severe phenotype. Twelve patients (9.0%) carried a duplication of the entire gene, as demonstrated by quantitative real-time PCR, and presented with a variable clinical phenotype including mild, classical, and severe courses of disease. Two patients had large deletions, spanning approximately 115 kb, that included the PLP1 gene. In total, we identified pathogenic mutations involving PLP1 in 35 (26.3%) of the 133 patients analyzed.

    Human mutation 2005;25;3;321-2

  • Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA.

    Hübner CA, Senning A, Orth U, Zerres K, Urbach H, Gal A and Rudnik-Schöneborn S

    Institute for Human Genetics, University Hospital Eppendorf, Hamburg, Germany.

    We describe a 28-year-old male patient with a mild course of Pelizaeus-Merzbacher disease (PMD) who presented with developmental delay in his second year of life and was able to walk until 12 years of age. Several computed tomography scans in infancy and youth were normal, the diagnosis of PMD was eventually suggested by magnetic resonance imaging at the age of 24 years. Analysis of the proteolipid protein gene (PLP1) revealed a nucleotide exchange (c.762G>T) at the 3' border of exon 6, which did not entail an amino acid exchange but adversely affected splicing. PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA. Exclusion of exon 6 does not alter the reading frame but leads to absence of amino acids 232-253 that constitute a main part of the fourth transmembrane helix of the PLP protein. Remarkably, residual wild-type splicing was also detected in the patient's cultured fibroblasts. This might explain the mild phenotype in this case, as exon 6 skipping mutations resulted in a severe course of disease in other patients.

    Neuroscience 2005;132;3;697-701

  • [Duplication of the PLP gene and the classical form of Pelizaeus-Merzbacher disease].

    Blanco-Barca MO, Eirís-Puñal J, Soler-Regal C and Castro-Gago M

    Servicio de Neuropediatría, Departamento de Pediatría, Hospital Clínico Universitario, Santiago de Compostela, España.

    Introduction: Pelizaeus-Merzbacher disease (PMD) is a rare form of sudanophilic leukodystrophy which is transmitted by recessive inheritance linked to the X chromosome. It only affects the myelin of the central nervous system (CNS) and is caused by a proteolipid protein (PLP) deficit, which is coded for in Xq21.2-q22. Presentation follows a classical or connatal pattern and is associated with nystagmus, stridor and pyramidal/extrapyramidal manifestations within the framework of a clinical picture of psychomotor retardation and regression with variable clinical course and presentation.

    A 37-month-old male, with sever psychomotor retardation, nystagmus and choreoathetotic movements with a stationary developmental profile. An MRI scan of the brain showed severe supratentorial hypomyelination and peripheral electrophysiological explorations (EMG and NCS) were normal. The genetic study using PCR revealed duplication in the PLP gene.

    Conclusion: This observation corresponds to a classical form of PMD, which must be taken into account when associated with: 1) Psychomotor retardation; 2) Early nystagmus; 3) Pyramidal/extrapyramidal involvement; 4) Absence of peripheral neurophysiological involvement; 5) A neuroradiological pattern of hypomyelination of the CNS.

    Revista de neurologia 2003;37;5;436-8

  • Myelination of a fetus with Pelizaeus-Merzbacher disease: immunopathological study.

    Shiraishi K, Itoh M, Sano K, Takashima S and Kubota T

    Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

    We report an autopsied case of a 21-gestational-week fetus with duplication of the proteolipid protein (PLP) gene (PLP1). An immunohistochemical study, which can detect the specific expression of PLP, myelin basic protein, myelin-associated glycoprotein, and platelet-derived growth factor receptor alpha subunit in brain tissues, showed that the myelination was almost the same as that of age-matched controls. This result suggests that the development and migration of the oligodendrocyte is normal in Pelizaeus-Merzbacher disease until midgestation. To our knowledge, this is the first report of the myelination of a fetus with duplication of the PLP1 gene.

    Annals of neurology 2003;54;2;259-62

  • Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease.

    Woodward K, Cundall M, Palmer R, Surtees R, Winter RM and Malcolm S

    Clinical and Molecular Genetics Unit, Institute of Child Health, London, United Kingdom. k.woodward@ich.ucl.ac.uk

    We report cytogenetic and molecular findings in a family in which Pelizaeus-Merzbacher disease has arisen by a sub-microscopic duplication of the proteolipid protein (PLP1) gene involving the insertion of approximately 600 kb from Xq22 into Xq26.3. The duplication arose in an asymptomatic mother on a paternally derived X chromosome and was inherited by her son, the proband, who is affected with Pelizaeus-Merzbacher disease. The mother also carries a large interstitial deletion of approximately 70 Mb extending from Xq21.1 to Xq27.3, which is present in a mosaic form. In lymphocytes, the mother has no normal cells, having one population with three copies of the PLP1gene (one normal X and one duplication X chromosome) and the other population having only one copy of the PLP1 gene (one normal X and one deleted X chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter --> Xq26.3::Xq22 --> Xq22::Xq26.3 --> Xqter)(PLP++)/46,X,del(X)(q21.1q27.3).ish del(X)(q21.1q27.3)(PLP-). Both ends of the deletion have been mapped by fluorescence in situ hybridization using selected DNA clones and neither involves the PLP1 gene or are in the vicinity of the duplication breakpoints. Prenatal diagnosis was carried out in a recent pregnancy and the complex counseling issues associated with these chromosomal rearrangements are discussed.

    American journal of medical genetics. Part A 2003;118A;1;15-24

  • Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.

    Shy ME, Hobson G, Jain M, Boespflug-Tanguy O, Garbern J, Sperle K, Li W, Gow A, Rodriguez D, Bertini E, Mancias P, Krajewski K, Lewis R and Kamholz J

    Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.

    Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.

    Funded by: NINDS NIH HHS: R01 NS043783

    Annals of neurology 2003;53;3;354-65

  • A severe connatal form of Pelizaeus Merzbacher disease in a Czech boy caused by a novel mutation (725C>A, Ala242Glu) at the 'jimpy(msd) codon' in the PLP gene.

    Seeman P, Paderova K, Benes V and Sistermans EA

    Department of Child Neurology, Second School of Medicine, Charles University and University Hospital Motol, Prague, 150 06 Prague 5, Czech Republic. pavel.seeman@lfmotol.cuni.cz

    Pelizaeus Merzbacher disease (PMD) is an X-linked recessive disorder of the central nervous system myelination caused by mutations involving the proteolipid protein gene (PLP). Early nystagmus and developmental delay, progressive pyramidal, cerebellar and dystonic signs as well as white matter changes in brain MRI are typical for PMD. The PLP gene can be affected by two major types of mutations. A duplication of the whole PLP gene is the most common mutation and results usually in the milder classical phenotype, whereas point mutations in PLP gene often result in the rarer and more severe connatal form of PMD. The PLP protein is a higly conserved across species and is identical in human, mouse and rat. We describe a 13-year-old Czech boy with an early and severe developmental delay. His maternal uncle died at the age of one year and was also early and severely psychomotoricly retarded. The patient was the first child of healthy unrelated parents born after an uneventful pregnancy and delivery in 1988. Hyperbilirubinemia and bronchopneumonia and early stridor complicated his neonatal period. Diffuse hypotonia, nystagmus, psychomotor retardation, visual and hearing impairment have been observed in the patient since the age of 6 weeks. White matter abnormalities, cortical and periventricular atrophy were detected by MRI at the age of 6 and 11 years, respectively. Despite these signs and results an accurate clinical diagnosis was unclear until the age of 11 years. Last neurological examination in 1999 showed no nystagmus anymore, but extremely dystrophic limbs, truncal deformation, due to severe scoliosis, tetraplegia with hyperreflexia in C5C7 and areflexia L2S2 and positive pyramidal signs. The boy had no visual or speech contact. DNA tests followed the clinical suspicion for PMD. At first, duplication of PLP gene was excluded by quantitative comparative PCR. Direct sequencing of PLP gene detected a novel mutation in exon 6, a missense mutation 725C-->A (Ala242Glu) in the patient and in his mother and later also in his maternal grandmother. The same codon, but to valine (Ala242Val) is mutated in jimpy(msd) mouse, which is the frequently used animal model for PMD. Prenatal diagnosis for the next pregnancy has been offered to the family. The patient died recently at the age of 13 years due to respiratory failure. Our results support the data on the importance of this conserved amino acid alanine at codon 242.

    International journal of molecular medicine 2002;9;2;125-9

  • Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease.

    Inoue K, Kanai M, Tanabe Y, Kubota T, Kashork CD, Wakui K, Fukushima Y, Lupski JR and Shaffer LG

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

    A submicroscopic genomic duplication in Xq22.2 that contains the entire proteolipid protein 1 gene (PLP1) is responsible for the majority of Pelizaeus-Merzbacher disease (PMD) patients. We previously developed an interphase FISH assay to screen for PLP1 duplications in PMD patients using peripheral blood and lymphoblastoid cell lines. This assay has been utilized as a clinical diagnostic test in our cytogenetics laboratory. To expand usage of the interphase FISH assay to prenatal diagnosis of PLP1 duplications, we examined three PMD families with PLP1 duplications utilizing aminiotic fluid samples. In two families the FISH assay revealed fetuses with PLP1 duplications, whereas the other fetus showed a normal copy number of PLP1. Haplotype analyses, as well as an additional FISH analysis using postnatal blood samples, confirmed the results of the prenatal analyses. Our study demonstrates utility of the interphase FISH assay in the prenatal diagnosis of PLP1 duplications in PMD.

    Funded by: NICHD NIH HHS: P30 HD24064; NINDS NIH HHS: R01 NS27042

    Prenatal diagnosis 2001;21;13;1133-6

  • Prenatal diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene duplication by quantitative fluorescent multiplex PCR.

    Regis S, Filocamo M, Mazzotti R, Cusano R, Corsolini F, Bonuccelli G, Stroppiano M and Gatti R

    Laboratorio di Diagnosi Pre e Postnatale di Malattie Metaboliche, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genoa, Italy. dppm@ospedale-gaslini.ge.it

    A prenatal diagnosis of Pelizaeus-Merzbacher disease (PMD) resulting from proteolipid protein gene (PLP) duplication was performed by a quantitative fluorescent multiplex PCR method. PLP gene copy number was determined in the proband, the pregnant mother, the male fetus and two aunts. Small amounts of genomic DNA extracted from peripheral blood and from chorionic villi were used. The fetus, in common with the proband, was identified as PMD-affected being a carrier of the PLP gene duplication, inherited from the mother, while the two aunts were non-carriers. The data obtained were confirmed by segregation analysis of a PLP-associated dinucleotide-repeat polymorphism amplified by the same multiplex PCR.

    Prenatal diagnosis 2001;21;8;668-71

  • A new polymorphism in the proteolipid protein (PLP1) gene and its use for carrier detection of PLP1 gene duplication in Pelizaeus-Merzbacher disease.

    Hobson G, Stabley D, Funanage V and Marks H

    Department of Research, Alfred I. DuPont Hospital for Children, Wilmington, DE, USA. ghobson@nemours.org

    Pelizaeus Merzbacher Disease (PMD) is an X-linked recessive dysmyelinating disorder of the central nervous system. Most patients have point mutations in exons of the proteolipid protein (PLP1) gene or duplication of a genomic region that includes the PLP1 gene. We identified a common MspI polymorphism in intron 1 of the PLP1 gene and used it to determine carrier status for PLP1 gene duplication in PMD by using a quantitative PCR approach.

    Human mutation 2001;17;2;152

  • A novel deletion (c663delC) at exon 5 of the proteolipid protein gene in Pelizaeus-Merzbacher disease.

    Matsumura T, Osaka H, Inoue K, Sugiyama N, Onishi H, Yamada Y, Hayashi M and Kosaka K

    Department of Psychiatry, School of Medicine, Yokohama City University, Tokyo, Japan.

    Human mutation 2001;17;1;80

  • Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease.

    Hobson GM, Davis AP, Stowell NC, Kolodny EH, Sistermans EA, de Coo IF, Funanage VL and Marks HG

    Department of Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19899, USA. ghobson@nemours.org

    Background: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of the proteolipid protein (PLP) gene are found in most patients.

    Objective: To describe five patients with PMD who have mutations in noncoding regions of the PLP gene.

    Methods: Quantitative multiplex PCR and Southern blot analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene.

    Results: Duplication of the PLP gene was ruled out, and mutations were identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IVS6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 months and progressive spastic ataxia at 18 months was found to have a 19-base pair (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19-bp deletion, are in intron 3, which is involved in PLP/DM20 alternative splice site selection.

    Conclusions: Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.

    Neurology 2000;55;8;1089-96

  • Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.

    Hodes ME, Woodward K, Spinner NB, Emanuel BS, Enrico-Simon A, Kamholz J, Stambolian D, Zackai EH, Pratt VM, Thomas IT, Crandall K, Dlouhy SR and Malcolm S

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA. mhodes@iupui.edu

    The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.

    Funded by: NICHD NIH HHS: HD26979, P30 HD026979

    American journal of human genetics 2000;67;1;14-22

  • MR-revealed myelination in the cerebral corticospinal tract as a marker for Pelizaeus-Merzbacher's disease with proteolipid protein gene duplication.

    Takanashi J, Sugita K, Tanabe Y, Nagasawa K, Inoue K, Osaka H and Kohno Y

    Department of Pediatrics, Faculty of Medicine, Chiba University, Chiba-shi, Japan.

    Pelizaeus-Merzbacher's disease (PMD) is caused by mutations in the proteolipid protein (PLP) gene. Recent studies have shown that an increased PLP dosage, resulting from total duplication of the PLP gene, invariably causes the classic form of PMD. The purpose of this study was to compare the MR findings of PMD attributable to PLP duplication with those of PMD arising from a missense mutation.

    Methods: Seven patients with PMD, three with a PLP missense mutation in either exon 2 or 5 (patients 1-3), and four with PLP duplication (patient 4 having larger PLP duplication than patients 5-7) were clinically classified as having either the classic or connatal form of PMD. Cerebral MR images were obtained to analyze the presence of myelination and T1 and T2 shortening in the deep gray matter. Multiple MR studies were performed in six of the seven patients to analyze longitudinal changes.

    Results: Four patients (patients 1-4) were classified as having connatal PMD, whereas the other three (patients 5-7) were classified as having classic PMD. Myelination in the cerebral corticospinal tract, optic radiation, and corpus callosum was observed in three cases of classic PMD with PLP duplication. In patient 4, myelination extended to the internal capsule, corona radiata, and centrum semiovale over a 3-year period. No myelination was observed in three PMD cases with a PLP point mutation. T2 shortening in the deep gray matter was recognized in all patients with PMD.

    Conclusion: The presence of myelination in the cerebral corticospinal tract with diffuse white matter hypomyelination on MR images could be a marker for PMD with PLP duplication. It is suggested that progression of myelination may be present in connatal PMD with large PLP duplication.

    AJNR. American journal of neuroradiology 1999;20;10;1822-8

  • A novel mutation (A246T) in exon 6 of the proteolipid protein gene associated with connatal Pelizaeus-Merzbacher disease.

    Yamamoto T and Nanba E

    Gene Research Center, Tottori University, Yonago 683-8503, Japan.

    Human mutation 1999;14;2;182

  • A de novo splice donor site mutation causes in-frame deletion of 14 amino acids in the proteolipid protein in Pelizaeus-Merzbacher disease.

    Aoyagi Y, Kobayashi H, Tanaka K, Ozawa T, Nitta H and Tsuji S

    Department of Neurology, Brain Research Institute, Niigata University, Japan.

    Pelizaeus-Merzbacher disease (PMD) is a leukodystrophy associated with mutations in the proteolipid protein (PLP) gene. Jimpy is a mouse model of human PMD, and a splice site mutation in Jimpy causes the deletion of exon 5 from the PLP mRNA, producing a truncated form of PLP. We describe a de novo point mutation at the 5' splice donor site of exon 5 in a 17-year-old male with PMD, which results in the skipping of 42 base pairs of exon 5. The mutation removes only 14 amino acids in-frame of PLP. This is a novel splice donor site mutation in the human PLP gene. Moreover, the results indicate that the 14-amino acid deletion in the PLP is responsible for oligodendrocyte cell death and the development of PMD.

    Annals of neurology 1999;46;1;112-5

  • Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2).

    Hodes ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA. mhodes@medgen.iupui.edu

    Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) comprises a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteolipid protein caused by certain amino acid substitutions and interference with the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine165 to either glutamate or glycine, leucine 045 to either proline or arginine, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appear in the A-B loop, C helix, and C-D loop, respectively. We describe clinically patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C667A (Leu223Ile). We discuss also the previously reported mutations Asp202Asn and Asp202His. We have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protein for the various mutations with the clinical data available on the patients. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than does Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains during myelin formation are probably at work.

    American journal of medical genetics 1999;82;2;132-9

  • Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease.

    Sistermans EA, de Coo RF, De Wijs IJ and Van Oost BA

    Department of Human Genetics, University Hospital Nijmegen, The Netherlands.

    Pelizaeus-Merzbacher disease (PMD), an X-linked recessive dysmyelination disorder, is caused by mutations in the proteolipid protein (PLP) gene. However, missense mutations were only found in a fraction of PMD patients, even in families that showed linkage with the PLP locus on Xq22. Here we describe the use of an extended protocol that includes screening for both missense mutations and duplications.

    Method: Two groups of patients were analyzed, one group with 10 independent PMD families and one group with 24 sporadic patients suspected of PMD. Missense mutations in the PLP gene were identified by sequencing. PLP gene duplications were detected by quantitative polymerase chain reaction and/or Southern blot analysis.

    Results: Sequencing of the PLP gene revealed four mutations in group 1 and one mutation in group 2. However, inclusion of duplication analysis in the screening protocol raised the amount of mutations found in group 1 from 40 to 90%, and in group 2 from 4 to 25%.

    Conclusions: These results demonstrate that duplications of the PLP gene are the major cause of PMD. Furthermore, it appears that the phenotype resulting from PLP duplications is relatively mild, and that many probands are nontypical PMD patients.

    Neurology 1998;50;6;1749-54

  • Family with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia and a nonsense mutation in exon 6 of the proteolipid protein gene.

    Bond C, Si X, Crisp M, Wong P, Paulson GW, Boesel CP, Dlouhy SR and Hodes ME

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We report on a C-to-T transition in exon 6 of the PLP gene in a male with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia. The transition changes a glutamine at amino acid residue 233 to a termination codon. This premature stop codon probably results in a truncated protein that is not functional. Six other relatives were analyzed for the mutation and two female carriers were identified. Autopsy data on one male are presented.

    Funded by: NICHD NIH HHS: 2T32HD07373

    American journal of medical genetics 1997;71;3;357-60

  • A new proteolipid lipoprotein mutation in Pelizaeus-Merzbacher disease.

    Verhagen WI, Huygen PL, Smeets HJ, Renier WO and de Wijs I

    Journal of the neurological sciences 1997;147;2;215-6

  • Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus-Merzbacher disease.

    Hodes ME, Blank CA, Pratt VM, Morales J, Napier J and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We report a G-->A transition at nucleotide 431 of the proteolipid protein gene (PLP) results in a nonsense codon in a family with an unusual form of Pelizaeus-Merzbacher disease (PMD). The mutation, which creates a second AluI restriction site, results in a nonsense mutation in PLP. The clinical picture resembles somewhat that of X-linked spastic paraplegia (SPG). It differs from this and both the classical and connatal forms of PMD in that it is relatively mild in form, onset is delayed beyond age 2 years, nystagmus is absent, tremors are prominent, mental retardation is not severe, some patients show dementia or personality disorders, the disease is progressive rather than static in some, and several females show signs of disease. The nonsense mutation, which is in exon 3B, should block the synthesis of normal PLP but spare DM20, the isoform whose persistence has been associated with mild forms of PLP-associated disease in both humans and mice.

    American journal of medical genetics 1997;69;2;121-5

  • Mutations in the proteolipid protein gene in Japanese families with Pelizaeus-Merzbacher disease.

    Inoue K, Osaka H, Kawanishi C, Sugiyama N, Ishii M, Sugita K, Yamada Y and Kosaka K

    Department of Psychiatry, Yokohama City University, School of Medicine, Japan.

    Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelinating disorder of the CNS resulting from abnormalities in the proteolipid protein (PLP) gene. Exonic mutations in the PLP gene are present in 10 to 25% of all cases. In investigating genotype-phenotype correlations, we screened five Japanese families with PMD for PLP gene mutations and compared their clinical manifestations. We identified two novel nucleotide substitutions in exon 5, at V208N and at P210L, in two families. In the remaining three families, there were no mutations detected. Although all patients satisfied the criteria for the classical form of PMD, two families not carrying the mutations showed milder clinical manifestations than those with the mutations. Since linkage analysis has shown homogeneity at the PLP locus in patients with PMD, our findings suggest that there may be genetic abnormalities other than exonic mutations that cause milder forms of PMD.

    Neurology 1997;48;1;283-5

  • A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family.

    Sistermans EA, de Wijs IJ, de Coo RF, Smit LM, Menko FH and van Oost BA

    Department of Human Genetics, University Hospital Nijmegen, The Netherlands.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder that is characterized by dysmyelination of the central nervous system resulting from mutations in the proteolipid protein (PLP) gene. Mutations causing either overexpression or expression of a truncated form of PLP result in oligodendrocyte cell death because of accumulation of PLP in the endoplasmic reticulum. It has therefore been hypothesized that absence of the protein should result in a less severe phenotype. However, until now, only one patient has been described with a complete deletion of the PLP gene. We report a Dutch family with a relatively mild form of PMD, in which the disease cosegregates with a (G-to-A) mutation in the initiation codon of the PLP gene. This mutation should cause the total absence of PLP and is therefore in agreement with the hypothesis that absence of PLP leads to a mild form of PMD.

    Human genetics 1996;97;3;337-9

  • Pelizaeus-Merzbacher disease caused by a de novo mutation that originated in exon 2 of the maternal great-grandfather of the propositus.

    Pratt VM, Boyadjiev S, Green K, Hodes ME and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder of the central nervous system. Many cases of PMD can be attributed to defects in the proteolipid protein gene (PLP). To date, with one exception, each family has had either no or a unique mutation in one of the seven exons of PLP. We describe a new missense mutation in exon 2 of the PLP gene of an affected individual. This mutation codes for Ile instead of Thr at codon 42. The point mutation originated in the X chromosome of the maternal great-grandfather of the propositus. This was determined from the pattern of inheritance of the AhaII polymorphism and a series of microsatellite markers that are localized near PLP at Xq22.

    American journal of medical genetics 1995;58;1;70-3

  • Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene.

    Hodes ME, DeMyer WE, Pratt VM, Edwards MK and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We studied a female infant with clinical signs of Pelizaeus-Merzbacher disease (PMD), who has a familial mutation (C41-->T) in exon 2 of the proteolipid protein gene (PLP), and selected relatives. While the carrier mother and grandmother of the proposita currently are neurologically normal and show normal T2 magnetic resonance imaging (MRI) of the brain, the infant has a neurological picture, MRIs, and brain auditory evoked response (BAER) consistent with that diagnosis. The data here presented show that PMD can occur in females carrying a mutation in the PLP gene. Our experience with the MRIs of this patient, her mother and grandmother, and those of a previously reported family [Pratt et al.: Am J Med Genet 38:136-139, 1991] show that molecular genetic analysis and not MRI is the appropriate means for carrier detection.

    American journal of medical genetics 1995;55;4;397-401

  • In-frame deletion in the proteolipid protein gene of a family with Pelizaeus-Merzbacher disease.

    Kleindorfer DO, Dlouhy SR, Pratt VM, Jones MC, Trofatter JA and Hodes ME

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We describe an in-frame deletion of parts of exons 3 and 4 of the proteolipid protein gene (PLP), with all of the intervening sequence, in a 3-generation family with Pelizaeus-Merzbacher disease. The mutation removes 49 amino acids of the PLP.

    American journal of medical genetics 1995;55;4;405-7

  • Pelizaeus-Merzbacher disease in a family of Portuguese origin caused by a point mutation in exon 5 of the proteolipid protein gene.

    Pratt VM, Boyadjiev S, Dlouhy SR, Silver K, Der Kaloustian VM and Hodes ME

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    Single-strand conformational polymorphism analysis of an affected male with Pelizaeus-Merzbacher disease (PMD) showed a slight change in mobility of amplified exon 5 of the proteolipid protein (PLP) gene. The exon was sequenced and a G-->A transition at codon 216 was found. This mutation eliminates a BstNI restriction site and creates a MaeI restriction site. In 1989, Gencic et al. reported a mutation that destroyed the same BstNI site, but resulted in a substitution at codon 215 [Am J Hum Genet 45:435-442]. The mutation we report here is also present in the patient's mother and her male fetus as determined by polymerase chain reaction analysis of amniocytes.

    American journal of medical genetics 1995;55;4;402-4

  • Pelizaeus-Merzbacher disease: a point mutation in exon 6 of the proteolipid protein (PLP) gene.

    Pratt VM, Dlouhy SR and Hodes ME

    Pelizaeus-Merzbacher disease has been known since 1885. It is characterized by severe dysmyelination of the central nervous system. We describe a new mutation in exon 6 of the proteolipid protein gene in a 9-year-old boy with severe connatal Pelizaeus-Merzbacher disease.

    Clinical genetics 1995;47;2;99-100

  • A G to T mutation at a splice site in a case of Pelizaeus-Merzbacher disease.

    Strautnieks S and Malcolm S

    Molecular Genetics Unit, Institute of Child Health, London, UK.

    Human molecular genetics 1993;2;12;2191-2

  • A novel insertional mutation at exon VII of the myelin proteolipid protein gene in Pelizaeus-Merzbacher disease.

    Kurosawa K, Iwaki A, Miyake S, Imaizumi K, Kuroki Y and Fukumaki Y

    Institute of Genetic Information, Kyushu University, Fukuoka, Japan.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked neurological disorder characterized by dysmyelination in the central nervous system (CNS). Recently mutations of the myelin proteolipid protein (PLP) gene which encodes both PLP and its isoform, DM-20 generated by alternative splicing, have been demonstrated in PMD patients. We analyzed the seven exons of the PLP gene of a Japanese boy affected with PMD by direct sequencing and identified an insertion event in exon VII of the PLP gene. This mutation was also present in his carrier mother, but was absent in ninety-five X chromosomes of normal Japanese. The frame-shift mutation leads to the production of truncated PLP with altered carboxyl terminal amino acid sequences, resulting in considerable change of the structure of PLP and DM-20 necessary for functional purposes. This is the first report of a mutation in exon VII of the PLP gene associated with PMD.

    Human molecular genetics 1993;2;12;2187-9

  • Linkage of a new mutation in the proteolipid protein (PLP) gene to Pelizaeus-Merzbacher disease (PMD) in a large Finnish kindred.

    Pratt VM, Kiefer JR, Lähdetie J, Schleutker J, Hodes ME and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251.

    The purpose of this study was to confirm linkage of the proteolipid protein gene (PLP) and Pelizaeus-Merzbacher disease (PMD). A T-->A transversion in nucleotide pair 35 of exon 4 of PLP was found in a large Finnish kindred with PMD. This mutation results in the substitution Val165-->Glu165. We used a combination of single-strand conformational polymorphism and PCR primer extension to determine the presence or absence of the point mutation in family members. A lod score of 2.6 (theta = 0) was found for linkage of the gene and the disease. We examined 101 unrelated X chromosomes and found none with the transversion. This is the second report of linkage of PMD to a missense mutation in PLP. These findings support the hypothesis that PMD in this family is a result of the missense mutation present in exon 4 of PLP.

    American journal of human genetics 1993;52;6;1053-6

  • Pelizaeus-Merzbacher disease: a frameshift deletion/insertion event in the myelin proteolipid gene.

    Pham-Dinh D, Boespflug-Tanguy O, Mimault C, Cavagna A, Giraud G, Leberre G, Lemarec B and Dautigny A

    Equipe ATIPE, URA 1488 CNRS, Paris, France.

    Among the central nervous system (CNS) dysmyelinating disorders, Pelizaeus-Merzbacher disease (PMD) has been individualized by its X-linked mode of inheritance and the existence of corresponding animal models. Mutations in the major myelin proteolipid (PLP) gene coding for PLP and its splicing variant DM20 protein, have been demonstrated in animal mutants and more recently in PMD affected patients. We have identified, in a two-generation PMD affected family, an insertion/deletion event in the exon IV of the PLP gene, leading to the synthesis of predicted truncated PLP and DM20 proteins with altered carboxyl terminal end. This is the first report of a frameshift mutation in the PLP gene in PMD.

    Human molecular genetics 1993;2;4;465-7

  • A novel mutation in the proteolipid protein gene leading to Pelizaeus-Merzbacher disease.

    Otterbach B, Stoffel W and Ramaekers V

    Institut für Biochemie, Medizinische Fakultät, Universität Köln.

    Point mutations of the gene of human proteolipid protein (PLP) have been recognized as the molecular basis of one form of leukodystrophy, the X-chromosome-linked Pelizaeus-Merzbacher disease (PMD). We report the molecular analysis of four PMD patients in three unrelated families and describe a point mutation (G-->A transition) in exon V which leads to the substitution of Gly216 by a serine residue in a highly conserved extracytosolic domain and a Mae I RFLP. Molecular modelling with energy minimization indicates that this seemingly minor alteration of the amino-acid sequence induces a considerable conformational change and tight packing of the polypeptide chain apparently not compatible with the regular PLP function in oligodendrocytes. This mutation has been detected and characterized by PCR amplification of genomic DNA using intron and exon primers and the complete sequence analysis of the seven exons and a 300 bp promoter region of the PLP gene of two affected brothers. The sequence analysis of a PCR fragment representing exon V amplified from genomic DNA of different kindreds of the pedigree revealed the mother as the only carrier indicating that the mutation has occurred de novo in the mother's germline. PLP gene (including the 8.8 kb intron I) rearrangements have been excluded by Southern blot hybridization and overlapping PCR amplification of genomic DNA.

    Biological chemistry Hoppe-Seyler 1993;374;1;75-83

  • Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease.

    Doll R, Natowicz MR, Schiffmann R and Smith FI

    Division of Biochemistry and Molecular Biology, Eunice K. Shriver Center for Mental Retardation, Waltham, MA 02254.

    Pelizaeus-Merzbacher disease (PMD) is a clinically heterogeneous, slowly progressive leukodystrophy. The recent detection of mutations in the myelin proteolipid protein (PLP) gene in several PMD patients offers the opportunity both to design DNA-based tests that would be useful in diagnosing a proportion of PMD cases and, in particular, to evaluate the diagnostic utility of single-strand conformation polymorphism (SSCP) analysis for this disease. A combination of SSCP analysis and direct sequencing of PCR-amplified DNA was used to screen for PLP mutations in 24 patients affected with leukodystrophies of unknown etiology. Two heretofore undescribed mutations in the PLP gene were identified, Asp202His in exon 4 and Gly73Arg in exon 3. The ease and efficiency of SSCP analysis in detecting new mutations support the utilization of this technique in screening for PLP mutations in patients with unexplained leukodystrophies.

    Funded by: NIDDK NIH HHS: DK38381

    American journal of human genetics 1992;51;1;161-9

  • New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease.

    Pratt VM, Trofatter JA, Larsen MB, Hodes ME and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School Medicine Indianapolis 46202-5251.

    A C--greater than G transversion has been found in exon 3 of the PLP gene of affected males and their mother in a single sibship with Pelizaeus-merzbacher disease (PMD). The transversion should not result in an amino acid change in the protein but it does result in the loss of a HaeIII restriction endonuclease cleavage site. It is concordant with the disease in this family. One-hundred-ten unrelated X chromosomes are negative for this mutation. No other sequence defect was found in the PLP exons of the affected males. The cause of disease in this family remains unknown, but the association between this rare mutation and PMD is intriguing. The mutation can serve as a marker for following segregation of the PLP gene.

    American journal of medical genetics 1992;43;3;642-6

  • Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease.

    Raskind WH, Williams CA, Hudson LD and Bird TD

    Department of Medicine, University of Washington School of Medicine, Seattle 98195.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked neurologic disorder characterized by dysmyelination in the central nervous system. Proteolipid protein (PLP), a major structural protein of myelin, is coded on the X chromosome. It has been postulated that a defect in the PLP gene is responsible for PMD. Different single-nucleotide substitutions have been found in conserved regions of the PLP gene of four unrelated PMD patients. Novel Southern blot patterns suggested a complex rearrangement in a fifth family. Linkage to PLP has been shown in others. We evaluated the PLP locus in a four-generation family with two living males affected with X-linked PMD. Analysis of DNA from the affected males revealed complete absence of a band, with PLP probes encompassing the promoter region, the entire coding region, and the 3' untranslated region and spanning at least 29 kb of genomic DNA. DNA from unaffected relatives gave the expected band pattern. Two obligate and one probable carrier women were hemizygous for the PLP locus by dosage analysis. Although it is unlikely, the previously described point mutations in PLP could represent polymorphisms. The finding of complete deletion of the PLP gene in our family is a stronger argument that mutations in PLP are responsible for X-linked PMD.

    Funded by: NCI NIH HHS: CA 16448

    American journal of human genetics 1991;49;6;1355-60

  • Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant.

    Trofatter JA, Dlouhy SR, DeMyer W, Conneally PM and Hodes ME

    Department of Medical Genetics, Indiana University Medical Center, Indianapolis 46223.

    Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred.

    Proceedings of the National Academy of Sciences of the United States of America 1989;86;23;9427-30

Literature (40)

Pubmed - human_disease

  • PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1.

    Combes P, Bonnet-Dupeyron MN, Gauthier-Barichard F, Schiffmann R, Bertini E, Rodriguez D, Armour JA, Boespflug-Tanguy O and Vaurs-Barrière C

    INSERM U 384, Faculté de Médecine, Place Henri Dunant, 63000 Clermont-Ferrand, France.

    The proteolipid protein 1 (PLP1) gene is known to be mutated in the X-linked disorders of myelin formation Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2. The most commonly found PLP1 mutations are gene duplications (60-70%) and point mutations (20%). About 20% of patients with a PMD phenotype do not present identified PLP1 mutation, thus suggesting genetic heterogeneity and/or undetected PLP1 abnormalities. Except the recently described MLPA screening the seven exonic regions, the currently used techniques to quantify PLP1 gene copy number do not investigate small intragenic PLP1 rearrangements. Using the multiplex amplifiable probe hybridization (MAPH) technique, we looked simultaneously for intragenic rearrangements along the PLP1 gene (exonic and regulatory regions) and for rearrangements in the GPM6B candidate gene (a member of the proteolipid protein family). We tested 262 hypomyelinating patients: 56 PLP1 duplicated patients, 1 PLP1 triplicated patient, and 205 patients presenting a leukodystrophy of undetermined origin with brain MRI suggesting a defect in myelin formation. Our results show that MAPH is an alternative reliable technique for diagnosis of PLP1 gene copy number. It allows us (1) to demonstrate that all PLP1 duplications previously found encompass the whole gene, (2) to establish that copy number changes in GPM6B and intragenic duplications of PLP1 are very unlikely to be involved in the etiology of UHL, and (3) to identify one partial triplication and two partial deletions of PLP1 in patients presenting with a PMD phenotype.

    Neurogenetics 2006;7;1;31-7

  • Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease.

    Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, Palmer R, Stubbs P, Davies S, Endziniene M, Wu Y, Chong WK, Malcolm S, Surtees R, Garbern JY and Woodward KJ

    Clinical and Molecular Genetics, Institute of Child Health, London, UK.

    We describe five boys from different families with an atypically severe form of Pelizaeus-Merzbacher disease (PMD) who have three, and in one case, five copies of the proteolipid protein (PLP1) gene. This is the first report of more than two copies of PLP1 in PMD patients and clearly demonstrates that severe clinical symptoms are associated with increased PLP1 gene dosage. Previously, duplications, deletions and mutations of the PLP1 gene were reported to give rise to this X-linked disorder. Patients with PLP1 duplication are usually classified as having either classical or transitional PMD rather than the more rare severe connatal form. The clinical symptoms of the five patients in this study included lack of stable head control and severe mental retardation, with three having severe paroxysmal disorder and two dying before the first year of life. Gene dosage was determined using interphase FISH (fluorescence in situ hybridization) and the novel approach of multiple ligation probe amplification (MLPA). We found FISH unreliable for dosage detection above the level of a duplication and MLPA to be more accurate in determination of specific copy number. Our finding that three or more copies of the gene give rise to a more severe phenotype is in agreement with observations in transgenic mice where severity of disease increased with Plp1 gene dosage and level of overexpression. The patient with five copies of PLP1 was not more affected than those with a triplication, suggesting that there is possibly a limit to the level of severity or that other genetic factors influence the phenotype. It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection.

    Brain : a journal of neurology 2005;128;Pt 4;743-51

  • [Duplication of the PLP gene and the classical form of Pelizaeus-Merzbacher disease].

    Blanco-Barca MO, Eirís-Puñal J, Soler-Regal C and Castro-Gago M

    Servicio de Neuropediatría, Departamento de Pediatría, Hospital Clínico Universitario, Santiago de Compostela, España.

    Introduction: Pelizaeus-Merzbacher disease (PMD) is a rare form of sudanophilic leukodystrophy which is transmitted by recessive inheritance linked to the X chromosome. It only affects the myelin of the central nervous system (CNS) and is caused by a proteolipid protein (PLP) deficit, which is coded for in Xq21.2-q22. Presentation follows a classical or connatal pattern and is associated with nystagmus, stridor and pyramidal/extrapyramidal manifestations within the framework of a clinical picture of psychomotor retardation and regression with variable clinical course and presentation.

    A 37-month-old male, with sever psychomotor retardation, nystagmus and choreoathetotic movements with a stationary developmental profile. An MRI scan of the brain showed severe supratentorial hypomyelination and peripheral electrophysiological explorations (EMG and NCS) were normal. The genetic study using PCR revealed duplication in the PLP gene.

    Conclusion: This observation corresponds to a classical form of PMD, which must be taken into account when associated with: 1) Psychomotor retardation; 2) Early nystagmus; 3) Pyramidal/extrapyramidal involvement; 4) Absence of peripheral neurophysiological involvement; 5) A neuroradiological pattern of hypomyelination of the CNS.

    Revista de neurologia 2003;37;5;436-8

  • Myelination of a fetus with Pelizaeus-Merzbacher disease: immunopathological study.

    Shiraishi K, Itoh M, Sano K, Takashima S and Kubota T

    Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

    We report an autopsied case of a 21-gestational-week fetus with duplication of the proteolipid protein (PLP) gene (PLP1). An immunohistochemical study, which can detect the specific expression of PLP, myelin basic protein, myelin-associated glycoprotein, and platelet-derived growth factor receptor alpha subunit in brain tissues, showed that the myelination was almost the same as that of age-matched controls. This result suggests that the development and migration of the oligodendrocyte is normal in Pelizaeus-Merzbacher disease until midgestation. To our knowledge, this is the first report of the myelination of a fetus with duplication of the PLP1 gene.

    Annals of neurology 2003;54;2;259-62

  • Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease.

    Woodward K, Cundall M, Palmer R, Surtees R, Winter RM and Malcolm S

    Clinical and Molecular Genetics Unit, Institute of Child Health, London, United Kingdom. k.woodward@ich.ucl.ac.uk

    We report cytogenetic and molecular findings in a family in which Pelizaeus-Merzbacher disease has arisen by a sub-microscopic duplication of the proteolipid protein (PLP1) gene involving the insertion of approximately 600 kb from Xq22 into Xq26.3. The duplication arose in an asymptomatic mother on a paternally derived X chromosome and was inherited by her son, the proband, who is affected with Pelizaeus-Merzbacher disease. The mother also carries a large interstitial deletion of approximately 70 Mb extending from Xq21.1 to Xq27.3, which is present in a mosaic form. In lymphocytes, the mother has no normal cells, having one population with three copies of the PLP1gene (one normal X and one duplication X chromosome) and the other population having only one copy of the PLP1 gene (one normal X and one deleted X chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter --> Xq26.3::Xq22 --> Xq22::Xq26.3 --> Xqter)(PLP++)/46,X,del(X)(q21.1q27.3).ish del(X)(q21.1q27.3)(PLP-). Both ends of the deletion have been mapped by fluorescence in situ hybridization using selected DNA clones and neither involves the PLP1 gene or are in the vicinity of the duplication breakpoints. Prenatal diagnosis was carried out in a recent pregnancy and the complex counseling issues associated with these chromosomal rearrangements are discussed.

    American journal of medical genetics. Part A 2003;118A;1;15-24

  • A severe connatal form of Pelizaeus Merzbacher disease in a Czech boy caused by a novel mutation (725C>A, Ala242Glu) at the 'jimpy(msd) codon' in the PLP gene.

    Seeman P, Paderova K, Benes V and Sistermans EA

    Department of Child Neurology, Second School of Medicine, Charles University and University Hospital Motol, Prague, 150 06 Prague 5, Czech Republic. pavel.seeman@lfmotol.cuni.cz

    Pelizaeus Merzbacher disease (PMD) is an X-linked recessive disorder of the central nervous system myelination caused by mutations involving the proteolipid protein gene (PLP). Early nystagmus and developmental delay, progressive pyramidal, cerebellar and dystonic signs as well as white matter changes in brain MRI are typical for PMD. The PLP gene can be affected by two major types of mutations. A duplication of the whole PLP gene is the most common mutation and results usually in the milder classical phenotype, whereas point mutations in PLP gene often result in the rarer and more severe connatal form of PMD. The PLP protein is a higly conserved across species and is identical in human, mouse and rat. We describe a 13-year-old Czech boy with an early and severe developmental delay. His maternal uncle died at the age of one year and was also early and severely psychomotoricly retarded. The patient was the first child of healthy unrelated parents born after an uneventful pregnancy and delivery in 1988. Hyperbilirubinemia and bronchopneumonia and early stridor complicated his neonatal period. Diffuse hypotonia, nystagmus, psychomotor retardation, visual and hearing impairment have been observed in the patient since the age of 6 weeks. White matter abnormalities, cortical and periventricular atrophy were detected by MRI at the age of 6 and 11 years, respectively. Despite these signs and results an accurate clinical diagnosis was unclear until the age of 11 years. Last neurological examination in 1999 showed no nystagmus anymore, but extremely dystrophic limbs, truncal deformation, due to severe scoliosis, tetraplegia with hyperreflexia in C5C7 and areflexia L2S2 and positive pyramidal signs. The boy had no visual or speech contact. DNA tests followed the clinical suspicion for PMD. At first, duplication of PLP gene was excluded by quantitative comparative PCR. Direct sequencing of PLP gene detected a novel mutation in exon 6, a missense mutation 725C-->A (Ala242Glu) in the patient and in his mother and later also in his maternal grandmother. The same codon, but to valine (Ala242Val) is mutated in jimpy(msd) mouse, which is the frequently used animal model for PMD. Prenatal diagnosis for the next pregnancy has been offered to the family. The patient died recently at the age of 13 years due to respiratory failure. Our results support the data on the importance of this conserved amino acid alanine at codon 242.

    International journal of molecular medicine 2002;9;2;125-9

  • Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease.

    Inoue K, Kanai M, Tanabe Y, Kubota T, Kashork CD, Wakui K, Fukushima Y, Lupski JR and Shaffer LG

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

    A submicroscopic genomic duplication in Xq22.2 that contains the entire proteolipid protein 1 gene (PLP1) is responsible for the majority of Pelizaeus-Merzbacher disease (PMD) patients. We previously developed an interphase FISH assay to screen for PLP1 duplications in PMD patients using peripheral blood and lymphoblastoid cell lines. This assay has been utilized as a clinical diagnostic test in our cytogenetics laboratory. To expand usage of the interphase FISH assay to prenatal diagnosis of PLP1 duplications, we examined three PMD families with PLP1 duplications utilizing aminiotic fluid samples. In two families the FISH assay revealed fetuses with PLP1 duplications, whereas the other fetus showed a normal copy number of PLP1. Haplotype analyses, as well as an additional FISH analysis using postnatal blood samples, confirmed the results of the prenatal analyses. Our study demonstrates utility of the interphase FISH assay in the prenatal diagnosis of PLP1 duplications in PMD.

    Funded by: NICHD NIH HHS: P30 HD24064; NINDS NIH HHS: R01 NS27042

    Prenatal diagnosis 2001;21;13;1133-6

  • Prenatal diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene duplication by quantitative fluorescent multiplex PCR.

    Regis S, Filocamo M, Mazzotti R, Cusano R, Corsolini F, Bonuccelli G, Stroppiano M and Gatti R

    Laboratorio di Diagnosi Pre e Postnatale di Malattie Metaboliche, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genoa, Italy. dppm@ospedale-gaslini.ge.it

    A prenatal diagnosis of Pelizaeus-Merzbacher disease (PMD) resulting from proteolipid protein gene (PLP) duplication was performed by a quantitative fluorescent multiplex PCR method. PLP gene copy number was determined in the proband, the pregnant mother, the male fetus and two aunts. Small amounts of genomic DNA extracted from peripheral blood and from chorionic villi were used. The fetus, in common with the proband, was identified as PMD-affected being a carrier of the PLP gene duplication, inherited from the mother, while the two aunts were non-carriers. The data obtained were confirmed by segregation analysis of a PLP-associated dinucleotide-repeat polymorphism amplified by the same multiplex PCR.

    Prenatal diagnosis 2001;21;8;668-71

  • A new polymorphism in the proteolipid protein (PLP1) gene and its use for carrier detection of PLP1 gene duplication in Pelizaeus-Merzbacher disease.

    Hobson G, Stabley D, Funanage V and Marks H

    Department of Research, Alfred I. DuPont Hospital for Children, Wilmington, DE, USA. ghobson@nemours.org

    Pelizaeus Merzbacher Disease (PMD) is an X-linked recessive dysmyelinating disorder of the central nervous system. Most patients have point mutations in exons of the proteolipid protein (PLP1) gene or duplication of a genomic region that includes the PLP1 gene. We identified a common MspI polymorphism in intron 1 of the PLP1 gene and used it to determine carrier status for PLP1 gene duplication in PMD by using a quantitative PCR approach.

    Human mutation 2001;17;2;152

  • A novel deletion (c663delC) at exon 5 of the proteolipid protein gene in Pelizaeus-Merzbacher disease.

    Matsumura T, Osaka H, Inoue K, Sugiyama N, Onishi H, Yamada Y, Hayashi M and Kosaka K

    Department of Psychiatry, School of Medicine, Yokohama City University, Tokyo, Japan.

    Human mutation 2001;17;1;80

  • Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease.

    Hobson GM, Davis AP, Stowell NC, Kolodny EH, Sistermans EA, de Coo IF, Funanage VL and Marks HG

    Department of Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19899, USA. ghobson@nemours.org

    Background: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of the proteolipid protein (PLP) gene are found in most patients.

    Objective: To describe five patients with PMD who have mutations in noncoding regions of the PLP gene.

    Methods: Quantitative multiplex PCR and Southern blot analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene.

    Results: Duplication of the PLP gene was ruled out, and mutations were identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IVS6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 months and progressive spastic ataxia at 18 months was found to have a 19-base pair (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19-bp deletion, are in intron 3, which is involved in PLP/DM20 alternative splice site selection.

    Conclusions: Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.

    Neurology 2000;55;8;1089-96

  • Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.

    Hodes ME, Woodward K, Spinner NB, Emanuel BS, Enrico-Simon A, Kamholz J, Stambolian D, Zackai EH, Pratt VM, Thomas IT, Crandall K, Dlouhy SR and Malcolm S

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA. mhodes@iupui.edu

    The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.

    Funded by: NICHD NIH HHS: HD26979, P30 HD026979

    American journal of human genetics 2000;67;1;14-22

  • MR-revealed myelination in the cerebral corticospinal tract as a marker for Pelizaeus-Merzbacher's disease with proteolipid protein gene duplication.

    Takanashi J, Sugita K, Tanabe Y, Nagasawa K, Inoue K, Osaka H and Kohno Y

    Department of Pediatrics, Faculty of Medicine, Chiba University, Chiba-shi, Japan.

    Pelizaeus-Merzbacher's disease (PMD) is caused by mutations in the proteolipid protein (PLP) gene. Recent studies have shown that an increased PLP dosage, resulting from total duplication of the PLP gene, invariably causes the classic form of PMD. The purpose of this study was to compare the MR findings of PMD attributable to PLP duplication with those of PMD arising from a missense mutation.

    Methods: Seven patients with PMD, three with a PLP missense mutation in either exon 2 or 5 (patients 1-3), and four with PLP duplication (patient 4 having larger PLP duplication than patients 5-7) were clinically classified as having either the classic or connatal form of PMD. Cerebral MR images were obtained to analyze the presence of myelination and T1 and T2 shortening in the deep gray matter. Multiple MR studies were performed in six of the seven patients to analyze longitudinal changes.

    Results: Four patients (patients 1-4) were classified as having connatal PMD, whereas the other three (patients 5-7) were classified as having classic PMD. Myelination in the cerebral corticospinal tract, optic radiation, and corpus callosum was observed in three cases of classic PMD with PLP duplication. In patient 4, myelination extended to the internal capsule, corona radiata, and centrum semiovale over a 3-year period. No myelination was observed in three PMD cases with a PLP point mutation. T2 shortening in the deep gray matter was recognized in all patients with PMD.

    Conclusion: The presence of myelination in the cerebral corticospinal tract with diffuse white matter hypomyelination on MR images could be a marker for PMD with PLP duplication. It is suggested that progression of myelination may be present in connatal PMD with large PLP duplication.

    AJNR. American journal of neuroradiology 1999;20;10;1822-8

  • A novel mutation (A246T) in exon 6 of the proteolipid protein gene associated with connatal Pelizaeus-Merzbacher disease.

    Yamamoto T and Nanba E

    Gene Research Center, Tottori University, Yonago 683-8503, Japan.

    Human mutation 1999;14;2;182

  • A de novo splice donor site mutation causes in-frame deletion of 14 amino acids in the proteolipid protein in Pelizaeus-Merzbacher disease.

    Aoyagi Y, Kobayashi H, Tanaka K, Ozawa T, Nitta H and Tsuji S

    Department of Neurology, Brain Research Institute, Niigata University, Japan.

    Pelizaeus-Merzbacher disease (PMD) is a leukodystrophy associated with mutations in the proteolipid protein (PLP) gene. Jimpy is a mouse model of human PMD, and a splice site mutation in Jimpy causes the deletion of exon 5 from the PLP mRNA, producing a truncated form of PLP. We describe a de novo point mutation at the 5' splice donor site of exon 5 in a 17-year-old male with PMD, which results in the skipping of 42 base pairs of exon 5. The mutation removes only 14 amino acids in-frame of PLP. This is a novel splice donor site mutation in the human PLP gene. Moreover, the results indicate that the 14-amino acid deletion in the PLP is responsible for oligodendrocyte cell death and the development of PMD.

    Annals of neurology 1999;46;1;112-5

  • Family with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia and a nonsense mutation in exon 6 of the proteolipid protein gene.

    Bond C, Si X, Crisp M, Wong P, Paulson GW, Boesel CP, Dlouhy SR and Hodes ME

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We report on a C-to-T transition in exon 6 of the PLP gene in a male with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia. The transition changes a glutamine at amino acid residue 233 to a termination codon. This premature stop codon probably results in a truncated protein that is not functional. Six other relatives were analyzed for the mutation and two female carriers were identified. Autopsy data on one male are presented.

    Funded by: NICHD NIH HHS: 2T32HD07373

    American journal of medical genetics 1997;71;3;357-60

  • A new proteolipid lipoprotein mutation in Pelizaeus-Merzbacher disease.

    Verhagen WI, Huygen PL, Smeets HJ, Renier WO and de Wijs I

    Journal of the neurological sciences 1997;147;2;215-6

  • Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus-Merzbacher disease.

    Hodes ME, Blank CA, Pratt VM, Morales J, Napier J and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We report a G-->A transition at nucleotide 431 of the proteolipid protein gene (PLP) results in a nonsense codon in a family with an unusual form of Pelizaeus-Merzbacher disease (PMD). The mutation, which creates a second AluI restriction site, results in a nonsense mutation in PLP. The clinical picture resembles somewhat that of X-linked spastic paraplegia (SPG). It differs from this and both the classical and connatal forms of PMD in that it is relatively mild in form, onset is delayed beyond age 2 years, nystagmus is absent, tremors are prominent, mental retardation is not severe, some patients show dementia or personality disorders, the disease is progressive rather than static in some, and several females show signs of disease. The nonsense mutation, which is in exon 3B, should block the synthesis of normal PLP but spare DM20, the isoform whose persistence has been associated with mild forms of PLP-associated disease in both humans and mice.

    American journal of medical genetics 1997;69;2;121-5

  • A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family.

    Sistermans EA, de Wijs IJ, de Coo RF, Smit LM, Menko FH and van Oost BA

    Department of Human Genetics, University Hospital Nijmegen, The Netherlands.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder that is characterized by dysmyelination of the central nervous system resulting from mutations in the proteolipid protein (PLP) gene. Mutations causing either overexpression or expression of a truncated form of PLP result in oligodendrocyte cell death because of accumulation of PLP in the endoplasmic reticulum. It has therefore been hypothesized that absence of the protein should result in a less severe phenotype. However, until now, only one patient has been described with a complete deletion of the PLP gene. We report a Dutch family with a relatively mild form of PMD, in which the disease cosegregates with a (G-to-A) mutation in the initiation codon of the PLP gene. This mutation should cause the total absence of PLP and is therefore in agreement with the hypothesis that absence of PLP leads to a mild form of PMD.

    Human genetics 1996;97;3;337-9

  • Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene.

    Hodes ME, DeMyer WE, Pratt VM, Edwards MK and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We studied a female infant with clinical signs of Pelizaeus-Merzbacher disease (PMD), who has a familial mutation (C41-->T) in exon 2 of the proteolipid protein gene (PLP), and selected relatives. While the carrier mother and grandmother of the proposita currently are neurologically normal and show normal T2 magnetic resonance imaging (MRI) of the brain, the infant has a neurological picture, MRIs, and brain auditory evoked response (BAER) consistent with that diagnosis. The data here presented show that PMD can occur in females carrying a mutation in the PLP gene. Our experience with the MRIs of this patient, her mother and grandmother, and those of a previously reported family [Pratt et al.: Am J Med Genet 38:136-139, 1991] show that molecular genetic analysis and not MRI is the appropriate means for carrier detection.

    American journal of medical genetics 1995;55;4;397-401

  • Pelizaeus-Merzbacher disease in a family of Portuguese origin caused by a point mutation in exon 5 of the proteolipid protein gene.

    Pratt VM, Boyadjiev S, Dlouhy SR, Silver K, Der Kaloustian VM and Hodes ME

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    Single-strand conformational polymorphism analysis of an affected male with Pelizaeus-Merzbacher disease (PMD) showed a slight change in mobility of amplified exon 5 of the proteolipid protein (PLP) gene. The exon was sequenced and a G-->A transition at codon 216 was found. This mutation eliminates a BstNI restriction site and creates a MaeI restriction site. In 1989, Gencic et al. reported a mutation that destroyed the same BstNI site, but resulted in a substitution at codon 215 [Am J Hum Genet 45:435-442]. The mutation we report here is also present in the patient's mother and her male fetus as determined by polymerase chain reaction analysis of amniocytes.

    American journal of medical genetics 1995;55;4;402-4

  • A G to T mutation at a splice site in a case of Pelizaeus-Merzbacher disease.

    Strautnieks S and Malcolm S

    Molecular Genetics Unit, Institute of Child Health, London, UK.

    Human molecular genetics 1993;2;12;2191-2

  • A novel insertional mutation at exon VII of the myelin proteolipid protein gene in Pelizaeus-Merzbacher disease.

    Kurosawa K, Iwaki A, Miyake S, Imaizumi K, Kuroki Y and Fukumaki Y

    Institute of Genetic Information, Kyushu University, Fukuoka, Japan.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked neurological disorder characterized by dysmyelination in the central nervous system (CNS). Recently mutations of the myelin proteolipid protein (PLP) gene which encodes both PLP and its isoform, DM-20 generated by alternative splicing, have been demonstrated in PMD patients. We analyzed the seven exons of the PLP gene of a Japanese boy affected with PMD by direct sequencing and identified an insertion event in exon VII of the PLP gene. This mutation was also present in his carrier mother, but was absent in ninety-five X chromosomes of normal Japanese. The frame-shift mutation leads to the production of truncated PLP with altered carboxyl terminal amino acid sequences, resulting in considerable change of the structure of PLP and DM-20 necessary for functional purposes. This is the first report of a mutation in exon VII of the PLP gene associated with PMD.

    Human molecular genetics 1993;2;12;2187-9

  • New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease.

    Pratt VM, Trofatter JA, Larsen MB, Hodes ME and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School Medicine Indianapolis 46202-5251.

    A C--greater than G transversion has been found in exon 3 of the PLP gene of affected males and their mother in a single sibship with Pelizaeus-merzbacher disease (PMD). The transversion should not result in an amino acid change in the protein but it does result in the loss of a HaeIII restriction endonuclease cleavage site. It is concordant with the disease in this family. One-hundred-ten unrelated X chromosomes are negative for this mutation. No other sequence defect was found in the PLP exons of the affected males. The cause of disease in this family remains unknown, but the association between this rare mutation and PMD is intriguing. The mutation can serve as a marker for following segregation of the PLP gene.

    American journal of medical genetics 1992;43;3;642-6

  • Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease.

    Raskind WH, Williams CA, Hudson LD and Bird TD

    Department of Medicine, University of Washington School of Medicine, Seattle 98195.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked neurologic disorder characterized by dysmyelination in the central nervous system. Proteolipid protein (PLP), a major structural protein of myelin, is coded on the X chromosome. It has been postulated that a defect in the PLP gene is responsible for PMD. Different single-nucleotide substitutions have been found in conserved regions of the PLP gene of four unrelated PMD patients. Novel Southern blot patterns suggested a complex rearrangement in a fifth family. Linkage to PLP has been shown in others. We evaluated the PLP locus in a four-generation family with two living males affected with X-linked PMD. Analysis of DNA from the affected males revealed complete absence of a band, with PLP probes encompassing the promoter region, the entire coding region, and the 3' untranslated region and spanning at least 29 kb of genomic DNA. DNA from unaffected relatives gave the expected band pattern. Two obligate and one probable carrier women were hemizygous for the PLP locus by dosage analysis. Although it is unlikely, the previously described point mutations in PLP could represent polymorphisms. The finding of complete deletion of the PLP gene in our family is a stronger argument that mutations in PLP are responsible for X-linked PMD.

    Funded by: NCI NIH HHS: CA 16448

    American journal of human genetics 1991;49;6;1355-60

Pubmed - other

  • Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination.

    Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, Howell G, Gribble SM, Burford DC, Carter NP, Hobson DL, Garbern JY, Kamholz J, Heng H, Hodes ME, Malcolm S and Hobson GM

    Clinical and Molecular Genetics, Institute of Child Health, London.

    We describe genomic structures of 59 X-chromosome segmental duplications that include the proteolipid protein 1 gene (PLP1) in patients with Pelizaeus-Merzbacher disease. We provide the first report of 13 junction sequences, which gives insight into underlying mechanisms. Although proximal breakpoints were highly variable, distal breakpoints tended to cluster around low-copy repeats (LCRs) (50% of distal breakpoints), and each duplication event appeared to be unique (100 kb to 4.6 Mb in size). Sequence analysis of the junctions revealed no large homologous regions between proximal and distal breakpoints. Most junctions had microhomology of 1-6 bases, and one had a 2-base insertion. Boundaries between single-copy and duplicated DNA were identical to the reference genomic sequence in all patients investigated. Taken together, these data suggest that the tandem duplications are formed by a coupled homologous and nonhomologous recombination mechanism. We suggest repair of a double-stranded break (DSB) by one-sided homologous strand invasion of a sister chromatid, followed by DNA synthesis and nonhomologous end joining with the other end of the break. This is in contrast to other genomic disorders that have recurrent rearrangements formed by nonallelic homologous recombination between LCRs. Interspersed repetitive elements (Alu elements, long interspersed nuclear elements, and long terminal repeats) were found at 18 of the 26 breakpoint sequences studied. No specific motif that may predispose to DSBs was revealed, but single or alternating tracts of purines and pyrimidines that may cause secondary structures were common. Analysis of the 2-Mb region susceptible to duplications identified proximal-specific repeats and distal LCRs in addition to the previously reported ones, suggesting that the unique genomic architecture may have a role in nonrecurrent rearrangements by promoting instability.

    Funded by: NCRR NIH HHS: P20 RR-020173-01, P20 RR020173; NINDS NIH HHS: NS043783, R01 NS043783; Wellcome Trust

    American journal of human genetics 2005;77;6;966-87

  • Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease.

    Hübner CA, Orth U, Senning A, Steglich C, Kohlschütter A, Korinthenberg R and Gal A

    Institute of Human Genetics, University Hospital Eppendorf, Hamburg, Germany. c.huebner@uke.uni-hamburg.de

    Pelizaeus-Merzbacher disease (PMD) is a rare X-chromosomal neurodegenerative disorder that affects primarily the white matter of the central nervous system and is caused by mutations of the PLP1 (proteolipid protein 1) gene. We performed mutation analysis of 133 male patients with suspected PMD. Following SSCP analysis of all coding exons of PLP1, we found most likely pathogenic mutations (single base substitutions and small rearrangements) including 17 novel sequence variants in 21 (15.8%) patients. Most patients with missense mutations had a severe phenotype. Twelve patients (9.0%) carried a duplication of the entire gene, as demonstrated by quantitative real-time PCR, and presented with a variable clinical phenotype including mild, classical, and severe courses of disease. Two patients had large deletions, spanning approximately 115 kb, that included the PLP1 gene. In total, we identified pathogenic mutations involving PLP1 in 35 (26.3%) of the 133 patients analyzed.

    Human mutation 2005;25;3;321-2

  • Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA.

    Hübner CA, Senning A, Orth U, Zerres K, Urbach H, Gal A and Rudnik-Schöneborn S

    Institute for Human Genetics, University Hospital Eppendorf, Hamburg, Germany.

    We describe a 28-year-old male patient with a mild course of Pelizaeus-Merzbacher disease (PMD) who presented with developmental delay in his second year of life and was able to walk until 12 years of age. Several computed tomography scans in infancy and youth were normal, the diagnosis of PMD was eventually suggested by magnetic resonance imaging at the age of 24 years. Analysis of the proteolipid protein gene (PLP1) revealed a nucleotide exchange (c.762G>T) at the 3' border of exon 6, which did not entail an amino acid exchange but adversely affected splicing. PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA. Exclusion of exon 6 does not alter the reading frame but leads to absence of amino acids 232-253 that constitute a main part of the fourth transmembrane helix of the PLP protein. Remarkably, residual wild-type splicing was also detected in the patient's cultured fibroblasts. This might explain the mild phenotype in this case, as exon 6 skipping mutations resulted in a severe course of disease in other patients.

    Neuroscience 2005;132;3;697-701

  • Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.

    Shy ME, Hobson G, Jain M, Boespflug-Tanguy O, Garbern J, Sperle K, Li W, Gow A, Rodriguez D, Bertini E, Mancias P, Krajewski K, Lewis R and Kamholz J

    Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.

    Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.

    Funded by: NINDS NIH HHS: R01 NS043783

    Annals of neurology 2003;53;3;354-65

  • Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2).

    Hodes ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA. mhodes@medgen.iupui.edu

    Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) comprises a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteolipid protein caused by certain amino acid substitutions and interference with the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine165 to either glutamate or glycine, leucine 045 to either proline or arginine, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appear in the A-B loop, C helix, and C-D loop, respectively. We describe clinically patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C667A (Leu223Ile). We discuss also the previously reported mutations Asp202Asn and Asp202His. We have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protein for the various mutations with the clinical data available on the patients. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than does Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains during myelin formation are probably at work.

    American journal of medical genetics 1999;82;2;132-9

  • Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease.

    Sistermans EA, de Coo RF, De Wijs IJ and Van Oost BA

    Department of Human Genetics, University Hospital Nijmegen, The Netherlands.

    Pelizaeus-Merzbacher disease (PMD), an X-linked recessive dysmyelination disorder, is caused by mutations in the proteolipid protein (PLP) gene. However, missense mutations were only found in a fraction of PMD patients, even in families that showed linkage with the PLP locus on Xq22. Here we describe the use of an extended protocol that includes screening for both missense mutations and duplications.

    Method: Two groups of patients were analyzed, one group with 10 independent PMD families and one group with 24 sporadic patients suspected of PMD. Missense mutations in the PLP gene were identified by sequencing. PLP gene duplications were detected by quantitative polymerase chain reaction and/or Southern blot analysis.

    Results: Sequencing of the PLP gene revealed four mutations in group 1 and one mutation in group 2. However, inclusion of duplication analysis in the screening protocol raised the amount of mutations found in group 1 from 40 to 90%, and in group 2 from 4 to 25%.

    Conclusions: These results demonstrate that duplications of the PLP gene are the major cause of PMD. Furthermore, it appears that the phenotype resulting from PLP duplications is relatively mild, and that many probands are nontypical PMD patients.

    Neurology 1998;50;6;1749-54

  • Mutations in the proteolipid protein gene in Japanese families with Pelizaeus-Merzbacher disease.

    Inoue K, Osaka H, Kawanishi C, Sugiyama N, Ishii M, Sugita K, Yamada Y and Kosaka K

    Department of Psychiatry, Yokohama City University, School of Medicine, Japan.

    Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelinating disorder of the CNS resulting from abnormalities in the proteolipid protein (PLP) gene. Exonic mutations in the PLP gene are present in 10 to 25% of all cases. In investigating genotype-phenotype correlations, we screened five Japanese families with PMD for PLP gene mutations and compared their clinical manifestations. We identified two novel nucleotide substitutions in exon 5, at V208N and at P210L, in two families. In the remaining three families, there were no mutations detected. Although all patients satisfied the criteria for the classical form of PMD, two families not carrying the mutations showed milder clinical manifestations than those with the mutations. Since linkage analysis has shown homogeneity at the PLP locus in patients with PMD, our findings suggest that there may be genetic abnormalities other than exonic mutations that cause milder forms of PMD.

    Neurology 1997;48;1;283-5

  • Pelizaeus-Merzbacher disease caused by a de novo mutation that originated in exon 2 of the maternal great-grandfather of the propositus.

    Pratt VM, Boyadjiev S, Green K, Hodes ME and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder of the central nervous system. Many cases of PMD can be attributed to defects in the proteolipid protein gene (PLP). To date, with one exception, each family has had either no or a unique mutation in one of the seven exons of PLP. We describe a new missense mutation in exon 2 of the PLP gene of an affected individual. This mutation codes for Ile instead of Thr at codon 42. The point mutation originated in the X chromosome of the maternal great-grandfather of the propositus. This was determined from the pattern of inheritance of the AhaII polymorphism and a series of microsatellite markers that are localized near PLP at Xq22.

    American journal of medical genetics 1995;58;1;70-3

  • In-frame deletion in the proteolipid protein gene of a family with Pelizaeus-Merzbacher disease.

    Kleindorfer DO, Dlouhy SR, Pratt VM, Jones MC, Trofatter JA and Hodes ME

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA.

    We describe an in-frame deletion of parts of exons 3 and 4 of the proteolipid protein gene (PLP), with all of the intervening sequence, in a 3-generation family with Pelizaeus-Merzbacher disease. The mutation removes 49 amino acids of the PLP.

    American journal of medical genetics 1995;55;4;405-7

  • Pelizaeus-Merzbacher disease: a point mutation in exon 6 of the proteolipid protein (PLP) gene.

    Pratt VM, Dlouhy SR and Hodes ME

    Pelizaeus-Merzbacher disease has been known since 1885. It is characterized by severe dysmyelination of the central nervous system. We describe a new mutation in exon 6 of the proteolipid protein gene in a 9-year-old boy with severe connatal Pelizaeus-Merzbacher disease.

    Clinical genetics 1995;47;2;99-100

  • Linkage of a new mutation in the proteolipid protein (PLP) gene to Pelizaeus-Merzbacher disease (PMD) in a large Finnish kindred.

    Pratt VM, Kiefer JR, Lähdetie J, Schleutker J, Hodes ME and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251.

    The purpose of this study was to confirm linkage of the proteolipid protein gene (PLP) and Pelizaeus-Merzbacher disease (PMD). A T-->A transversion in nucleotide pair 35 of exon 4 of PLP was found in a large Finnish kindred with PMD. This mutation results in the substitution Val165-->Glu165. We used a combination of single-strand conformational polymorphism and PCR primer extension to determine the presence or absence of the point mutation in family members. A lod score of 2.6 (theta = 0) was found for linkage of the gene and the disease. We examined 101 unrelated X chromosomes and found none with the transversion. This is the second report of linkage of PMD to a missense mutation in PLP. These findings support the hypothesis that PMD in this family is a result of the missense mutation present in exon 4 of PLP.

    American journal of human genetics 1993;52;6;1053-6

  • Pelizaeus-Merzbacher disease: a frameshift deletion/insertion event in the myelin proteolipid gene.

    Pham-Dinh D, Boespflug-Tanguy O, Mimault C, Cavagna A, Giraud G, Leberre G, Lemarec B and Dautigny A

    Equipe ATIPE, URA 1488 CNRS, Paris, France.

    Among the central nervous system (CNS) dysmyelinating disorders, Pelizaeus-Merzbacher disease (PMD) has been individualized by its X-linked mode of inheritance and the existence of corresponding animal models. Mutations in the major myelin proteolipid (PLP) gene coding for PLP and its splicing variant DM20 protein, have been demonstrated in animal mutants and more recently in PMD affected patients. We have identified, in a two-generation PMD affected family, an insertion/deletion event in the exon IV of the PLP gene, leading to the synthesis of predicted truncated PLP and DM20 proteins with altered carboxyl terminal end. This is the first report of a frameshift mutation in the PLP gene in PMD.

    Human molecular genetics 1993;2;4;465-7

  • A novel mutation in the proteolipid protein gene leading to Pelizaeus-Merzbacher disease.

    Otterbach B, Stoffel W and Ramaekers V

    Institut für Biochemie, Medizinische Fakultät, Universität Köln.

    Point mutations of the gene of human proteolipid protein (PLP) have been recognized as the molecular basis of one form of leukodystrophy, the X-chromosome-linked Pelizaeus-Merzbacher disease (PMD). We report the molecular analysis of four PMD patients in three unrelated families and describe a point mutation (G-->A transition) in exon V which leads to the substitution of Gly216 by a serine residue in a highly conserved extracytosolic domain and a Mae I RFLP. Molecular modelling with energy minimization indicates that this seemingly minor alteration of the amino-acid sequence induces a considerable conformational change and tight packing of the polypeptide chain apparently not compatible with the regular PLP function in oligodendrocytes. This mutation has been detected and characterized by PCR amplification of genomic DNA using intron and exon primers and the complete sequence analysis of the seven exons and a 300 bp promoter region of the PLP gene of two affected brothers. The sequence analysis of a PCR fragment representing exon V amplified from genomic DNA of different kindreds of the pedigree revealed the mother as the only carrier indicating that the mutation has occurred de novo in the mother's germline. PLP gene (including the 8.8 kb intron I) rearrangements have been excluded by Southern blot hybridization and overlapping PCR amplification of genomic DNA.

    Biological chemistry Hoppe-Seyler 1993;374;1;75-83

  • Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease.

    Doll R, Natowicz MR, Schiffmann R and Smith FI

    Division of Biochemistry and Molecular Biology, Eunice K. Shriver Center for Mental Retardation, Waltham, MA 02254.

    Pelizaeus-Merzbacher disease (PMD) is a clinically heterogeneous, slowly progressive leukodystrophy. The recent detection of mutations in the myelin proteolipid protein (PLP) gene in several PMD patients offers the opportunity both to design DNA-based tests that would be useful in diagnosing a proportion of PMD cases and, in particular, to evaluate the diagnostic utility of single-strand conformation polymorphism (SSCP) analysis for this disease. A combination of SSCP analysis and direct sequencing of PCR-amplified DNA was used to screen for PLP mutations in 24 patients affected with leukodystrophies of unknown etiology. Two heretofore undescribed mutations in the PLP gene were identified, Asp202His in exon 4 and Gly73Arg in exon 3. The ease and efficiency of SSCP analysis in detecting new mutations support the utilization of this technique in screening for PLP mutations in patients with unexplained leukodystrophies.

    Funded by: NIDDK NIH HHS: DK38381

    American journal of human genetics 1992;51;1;161-9

  • Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant.

    Trofatter JA, Dlouhy SR, DeMyer W, Conneally PM and Hodes ME

    Department of Medical Genetics, Indiana University Medical Center, Indianapolis 46223.

    Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred.

    Proceedings of the National Academy of Sciences of the United States of America 1989;86;23;9427-30

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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