G2Cdb::Human Disease report

Disease id
D00000195
Name
Multiple sclerosis
Nervous system disease
yes

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001807 MBP
myelin basic protein
Y (1383661) Unknown (?) Y
G00001807 MBP
myelin basic protein
Y (1691612) Restriction fragment length polymorphism (RFLP) Y
G00001807 MBP
myelin basic protein
Y (7515903) Repeat polymorphism (RP) N
G00001807 MBP
myelin basic protein
Y (7523603) Amplification fragment length polymorphism (AmpFLP) N
G00001807 MBP
myelin basic protein
Y (7530769) Unknown (?) N
G00001807 MBP
myelin basic protein
Y (7561955) Unknown (?) Y
G00001807 MBP
myelin basic protein
Y (7685461) Microsatellite variation (MSV) N
G00001807 MBP
myelin basic protein
Y (8739431) Repeat polymorphism (RP) Y
G00001807 MBP
myelin basic protein
Y (9345452) Repeat polymorphism (RP) N
G00001807 MBP
myelin basic protein
Y (9460711) Single nucleotide polymorphism (SNP) N
G00001807 MBP
myelin basic protein
Y (9482678) Repeat polymorphism (RP) N
G00001807 MBP
myelin basic protein
Y (10871781) Deletion (D) Y
G00001807 MBP
myelin basic protein
Y (10871781) Polymorphism (P) Y
G00001807 MBP
myelin basic protein
Y (12939427) Repeat polymorphism (RP) Y
G00001806 PLP1
proteolipid protein 1
Y (7504548) Insertion (I) N
G00001806 PLP1
proteolipid protein 1
Y (16130097) Microinsertion (MI) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (14759629) Microsatellite polymorphism (MSP) N

References

  • Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation.

    Warshawsky I, Rudick RA, Staugaitis SM and Natowicz MR

    Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

    We report a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and cerebrospinal fluid immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis and whose son died at age 10 years of an unknown congenital neurodevelopmental disorder. Sequencing of the proteolipid protein 1 gene showed a novel mutation, Leu30Arg (c.89TG), in the mother and son. Pelizaeus-Merzbacher disease is the cause of death in the son and explains the mother's adult-onset neurological disorder. This case goes against dogma that mothers of severely affected sons are asymptomatic as adults and expands the differential diagnosis of primary progressive multiple sclerosis to include proteolipid protein 1 gene mutations.

    Annals of neurology 2005;58;3;470-3

  • Investigation of a neuronal nitric oxide synthase gene (NOS1) polymorphism in a multiple sclerosis population.

    Tajouri L, Ferreira L, Ovcaric M, Curtain R, Lea R, Csurhes P, Pender MP and Griffiths LR

    Genomics Research Centre, School of Health Science, Griffith University Gold Coast, Southport, Queensland, 4215 Australia.

    Multiple Sclerosis (MS) is a chronic neurological disease characterized by demyelination associated with infiltrating white blood cells in the central nervous system (CNS). Nitric oxide synthases (NOS) are a family of enzymes that control the production of nitric oxide. It is possible that neuronal NOS could be involved in MS pathophysiology and hence the nNOS gene is a potential candidate for involvement in disease susceptibility. The aim of this study was to determine whether allelic variation at the nNOS gene locus is associated with MS in an Australian cohort. DNA samples obtained from a Caucasian Australian population affected with MS and an unaffected control population, matched for gender, age and ethnicity, were genotyped for a microsatellite polymorphism in the promoter region of the nNOS gene. Allele frequencies were compared using chi-squared based statistical analyses with significance tested by Monte Carlo simulation. Allelic analysis of MS cases and controls produced a chi-squared value of 5.63 with simulated P = 0.96 (OR(max) = 1.41, 95% CI: 0.926-2.15). Similarly, a Mann-Whitney U analysis gave a non-significant P-value of 0.377 for allele distribution. No differences in allele frequencies were observed for gender or clinical course subtype (P > 0.05). Statistical analysis indicated that there is no association of this nNOS variant and MS and hence the gene does not appear to play a genetically significant role in disease susceptibility.

    Journal of the neurological sciences 2004;218;1-2;25-8

  • Myelin basic protein gene is associated with MS in DR4- and DR5-positive Italians and Russians.

    Guerini FR, Ferrante P, Losciale L, Caputo D, Lombardi ML, Pirozzi G, Luongo V, Sudomoina MA, Andreewski TV, Alekseenkov AD, Boiko AN, Gusev EI and Favorova OO

    Laboratory of Biology, Don C. Gnocchi Foundation, ONLUS, IRCCS, Italy.

    Background: The myelin basic protein (MBP) gene may confer genetic susceptibility to multiple sclerosis (MS). The association of MS with alleles of the (TGGA)n variable number tandem repeat (VNTR) 5' to the MBP gene is the subject of conflicting reports.

    Objective: To study possible MS association with VNTR alleles of MBP gene in ethnic Italians and ethnic Russians.

    Methods: Two hundred sixty-nine unrelated patients with definite MS and 385 unrelated healthy control subjects from Italy and Russia were genotyped for the MBP VNTR region and for the human leukocyte antigen (HLA) class II DRB1 gene. The phenotype, allele, and genotype frequencies for two groups of MBP alleles were determined. Patients and control subjects were stratified according to HLA-DRB1 phenotypes.

    Results: The distribution of MBP alleles and genotypes in the two ethnic groups, including both MS patients and control subjects, was very similar. When MS patients and healthy control subjects were stratified according to HLA-DRB1 phenotypes, a significant association of MS with MBP alleles was found only in the DR4- and DR5-positive subgroups. A significant association with MBP alleles was also observed in the nonstratified groups, owing mainly to the contribution of the DR4- and DR5-positive individuals.

    Conclusion: Polymorphism of the MBP or another gene in its vicinity appears to contribute to the etiology of MS for the subgroups of DR4- and DR5-positive Italians and Russians.

    Neurology 2003;61;4;520-6

  • A polymorphism in the repetitive (TGGA)n sequence 5' to the human myelin basic protein gene in Italian multiple sclerosis patients.

    Guerini FR, Losciale L, Mediati M, Speciale L, Mancuso R, Saresella M, Calvo MG, Caputo D and Ferrante P

    Laboratory of Biology, Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.

    Human myelin basic protein (hMBP) gene is one of the candidate genes in the complex mosaic of multiple sclerosis (MS) susceptibility. In this study we verified the distribution of the polymorphism of the region 5' flanking the first exon of the hMBP gene, in 97 relapsing remitting, 74 primary progressive Italian MS patients, and in 236 healthy controls, using polymerase chain reaction (PCR) and gel electrophoresis analysis in this region from 1116 - 1540 nt. Three different band patterns were observed: one homozygote with a 354 bp long fragment, one homozygote with 424 bp long fragment and one heterozygote with both bands present. The short fragment was statistically more frequent in RRMS patients than in HC (P<0.05). The long fragment was more present in HC. Similarly the short homozygous pattern (354 bp/354 bp) was significantly higher in the RRMS patients versus the healthy controls (P<0.01). The sequence analysis of the hMBP alleles showed that while the long fragments matched the prototype sequence completely, all the short fragments showed a deletion of 70 bp from nt 1177 to nt 1247, which explains the short 354 bp allele detected by PCR. Moreover two single mismatches in positions 1386 (T-->C) and 1431 (G-->A), were present only in the short hMBP fragment.

    Journal of neurovirology 2000;6 Suppl 2;S28-32

  • The myelin basic protein gene in multiple sclerosis: identification of discrete alleles of a 1.3 kb tetranucleotide repeat sequence.

    He B, Yang B, Lundahl J, Fredrikson S and Hillert J

    Department of Neurology, NOVUM, Karolinska Institute at Huddinge University Hospital, Sweden.

    Myelin basic protein (MBP) is a potential autoantigen in multiple sclerosis (MS) and its gene therefore is an attractive candidate to confer genetic susceptibility to this disease. Linkage and association with certain alleles of a 1.2 kb tetranucleotide repeat region 5' to the MBP gene with MS have been reported in Finnish patients, and an association has been reported from Denmark. However, these findings have not been confirmed in subsequent analyses in other populations. A limitation of previous studies has been the low resolution of the typing procedure. We have investigated the same polymorphism in thirty-four Swedish nuclear families with 2 or 3 MS patients. and in 149 unrelated Swedish MS patients and 95 healthy controls using a fluorescence-based semi-automated technique which allowed the identification of discrete tetrarepeat numbers. Neither parametric two-point linkage analysis nor a nonparametric affected pedigree members analysis showed any sign of linkage. In addition, the distribution of alleles was similar in patients and controls. We conclude that the MBP gene does not influence susceptibility to MS in Swedish patients.

    Acta neurologica Scandinavica 1998;97;1;46-51

  • Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences.

    Price SE, Sharpe G, Boots A, Poutsma A, Mason C, James J, Hinks L and Thompson RJ

    Wessex Human Genetics Institute, Southampton General Hospital, UK.

    Susceptibility to multiple sclerosis (MS) is widely held to have a strong genetic component. While the identities of genes conferring susceptibility are currently unknown, possible candidates include those genes coding for proteins which function in central nervous system (CNS) myelin. Two such genes are the human myelin basic protein (MBP) and proteolipid protein (PLP) genes, whose products make up approximately 80% of the total protein in CNS myelin. The association of a variable number tandem repeat (VNTR) 5' to the human MBP gene with MS has been the subject of conflicting reports. Here we test the hypothesis that mutations in the human MBP and PLP genes might be associated with MS by examining the entire expressed sequence of both genes by single strand conformation polymorphism (SSCP) analysis, using a panel of 71 MS patients and 71 controls. We have also re-examined the VNTR region in patients and controls. Three base changes were found in the human PLP gene and nine base changes in the human MBP gene; these were essentially equally distributed between patients and controls. No preferential distribution of various alleles of the VNTR between patients and controls was found. Although intronic and regulatory regions have not been examined, it would appear unlikely that mutations in these genes coding for the two major CNS myelin proteins contribute significantly to genetic susceptibility to MS.

    Neuropathology and applied neurobiology 1997;23;6;457-67

  • A repetitive DNA sequence 5' to the human myelin basic protein gene may be linked to MS in Danes.

    Ibsen SN and Clausen J

    Department for Life Sciences and Chemistry, Roskilde University, Denmark.

    The myelin basic protein (MBP) gene is a candidate locus for disease susceptibility in multiple sclerosis (MS). In the present study a part of the tetranucleotide (TGGA)n repeat polymorphism 5' to the MBP gene was examined in 90 Danish MS patients and 106 controls. Lymphocyte DNA was isolated and used in PCR assay. The PCR fragments produced were separated by agarose and acrylamide electrophoresis. Hereby we found three different bandpatterns i.e. a homozygote with a 450 bp fragment, a homozygote with a fragment 375 bp and a heterozygote with both bands present. The 450 bp fragment occurred significantly more often among MS than in the control group and the 375 bp fragment was underrepresented among MS than in the control group. The differences between incidence of the three band pattern in the MS and the control group were significant different at 1% level. Our study thus indicate that there is an association between MS and a length polymorphism of the 5' end to the MBP gene in Danish MS patients.

    Acta neurologica Scandinavica 1996;93;4;236-40

  • PCR typing of two short tandem repeat (STR) structures upstreams of the human myelin basic protein (MBP) gene; the genetic susceptibility in multiple sclerosis and monosymptomatic idiopathic optic neuritis in Danes.

    Nellemann LJ, Frederiksen J and Morling N

    Department of Forensic Genetics, University of Copenhagen, Denmark.

    We investigated two short tandem tetranucleotide (TGGA) repeat polymorphisms upstreams of the myelin basic protein (MBP) gene. The region was amplified by the polymerase chain reaction (PCR) and the two repeat systems were separated by cutting with the restriction enzyme NlaIII. The lengths of the DNA fragments were analyzed by vertical electrophoresis in polyacrylamide gels followed by silver staining. We compared the DNA fragment frequencies of the two MBP regions in 34 patients suffering from multiple sclerosis and in 78 suffering from monosymptomatic idiopathic optic neuritis to those in 200 healthy controls. We found no significant differences between the MBP fragment frequencies in either of the patient groups and in the control group.

    Multiple sclerosis (Houndmills, Basingstoke, England) 1995;1;3;186-9

  • Genetic susceptibility to multiple sclerosis may be linked to polymorphism of the myelin basic protein gene.

    Ibsen SN and Clausen J

    Department for Life Sciences and Chemistry, Roskilde University, Denmark.

    The present paper compares the genetic polymorphism of a part of the myelin basic protein (MBP) gene in 64 Danish MS patients with that of 57 normal controls. PCR analysis, using primers flanking the 5' area from 479 to 1812 bp upstream the initiator methionine in the MBP gene, revealed that genetic susceptibility to MS is linked to polymorphism in the part of the MBP gene studied. Thus we found three different band patterns i.e. a homozygote with a 1445 bp long fragment, a homozygote with a fragment 1318 bp long and a heterozygote with both bands present. 59% of 64 patients with MS were homozygous for 1.445 kb allele, versus 40% of 57 control subjects, 18% of the control subjects were homozygous for the 1.318 kb, while only 0.7% of the MS patients possessed this allele. The differences between incidence of the three band pattern in the MS and the control group were significant at 1% level. Validation analysis furthermore support, the view that the 1445 bp PCR fragment is associated with MS.

    Journal of the neurological sciences 1995;131;1;96-8

  • The myelin basic protein gene is not a major susceptibility locus for multiple sclerosis in Italian patients.

    Eoli M, Pandolfo M, Milanese C, Gasparini P, Salmaggi A and Zeviani M

    2nd Division of Neurology, Istituto Nazionale Neurologico C. Besta, Milan, Italy.

    To verify whether multiallelic polymorphism adjacent to the gene encoding for myelin basic protein is associated with or linked to multiple sclerosis in Italians, we studied 54 sporadic patients, 55 control subjects and 18 families with two or more affected individuals. Allelic typing was carried out by analysis of fragment length polymorphisms after DNA amplification by the polymerase chain reaction. The presence of linkage with the disease was tested according to either autosomal dominant or autosomal recessive modes of inheritance, and with or without the introduction of liability classes accounting for the age of the individuals. Furthermore sib-pair analysis was performed in 11 siblings. No evidence for association or linkage between the myelin basic protein gene polymorphism and multiple sclerosis was found. Our data indicate that in the Italian population the myelin basic protein gene does not play a major role in conferring genetic susceptibility to multiple sclerosis, and suggest that the latter is a heterogeneous phenomenon, possibly influenced by the different ethnic origin of the populations which have been investigated.

    Journal of neurology 1994;241;10;615-9

  • No linkage or association between multiple sclerosis and the myelin basic protein gene in affected sibling pairs.

    Wood NW, Holmans P, Clayton D, Robertson N and Compston DA

    University of Cambridge Neurology unit, Addenbrooke's Hospital, UK.

    Myelin basic protein was examined as a candidate gene for susceptibility to multiple sclerosis using two adjacent amplification fragment length polymorphisms (AmpFLPs), containing seven and six highly informative alleles respectively. No allelic association was found with multiple sclerosis, comparing 77 cases and 88 controls, and there was no evidence for linkage in 73 affected sibling pairs, using the methods of identity by descent and identity by state.

    Journal of neurology, neurosurgery, and psychiatry 1994;57;10;1191-4

  • Myelin basic protein gene polymorphism is not associated with chronic progressive multiple sclerosis.

    Vandevyver C, Stinissen P, Cassiman JJ and Raus J

    Department of Immunology/Biotechnology, Dr. L. Willems-Instituut at Diepenbeek, Belgium.

    In the present study a tetranucleotide (TGGA)n repeat polymorphism 5' to the myelin basic protein (MBP) gene was evaluated in a group of HLA-class II-typed, chronic progressive multiple sclerosis (MS) patients. This polymorphism has been reported by others to be associated with MS. Contrary to these reports we observed similar allele frequencies in patients and controls. Our results indicate that there is no association between MS and a polymorphism 5' to the MBP gene.

    Journal of neuroimmunology 1994;52;1;97-9

  • Identification of a new polymorphism in the human proteolipid protein gene.

    Poduslo SE, Decker P, Astle H, Kurth J and LaBate M

    Department of Neurology, Texas Tech University Health Sciences Center, Lubbock 79430.

    A polymorphism in the gene for proteolipid protein has been identified, using amplification by the polymerase chain reaction, restriction enzyme digestion, and fragment separation by polyacrylamide gel electrophoresis. The polymorphism is located in the transcribed 3'-untranslated region, a region with potential regulatory signals. The mutation consists of a single base pair insertion into a Hae III restriction site, producing a larger rare fragment of 409 bp as compared with the more frequent 325 bp fragment. The gene for proteolipid protein is on the X chromosome; thus the males are hemizygous for the rare allele and the females are heterozygous carriers. The polymorphism occurs with a frequency of 0.046 in a population of European origin and also has a rare frequency in multiple sclerosis patients.

    Neurochemistry international 1993;23;5;413-7

  • Lack of association between myelin basic protein gene microsatellite and multiple sclerosis.

    Graham CA, Kirk CW, Nevin NC, Droogan AG, Hawkins SA, McMillan SA and McNeill TA

    Lancet (London, England) 1993;341;8860;1596

  • Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene.

    Tienari PJ, Wikström J, Sajantila A, Palo J and Peltonen L

    Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.

    Genetic factors have been implicated in the aetiology of multiple sclerosis (MS), but the genes conferring susceptibility to MS have not been identified. We carried out genetic linkage and association analyses by studying polymorphism of the myelin basic protein (MBP) gene on chromosome 18, a candidate gene for MS, in 21 MS families, 51 additional unrelated patients with definite MS, and 85 controls. All subjects were Finnish, and 14 of the families were from an area with an exceptional familial clustering of MS. Magnetic resonance imaging (MRI) was used to examine subclinical disease in symptom-free family members. In the association analysis, the allele frequencies between MS patients and controls differed significantly, p = 0.000049), the difference being attributable mainly to a higher frequency of a 1.27 kb allele among patients. In the linkage analysis, based on an autosomal dominant model and penetrance 0.05, a maximum LOD score of 3.42 (theta = 0.00) was obtained when patients with optic neuritis and their symptom-free siblings with abnormal MRI findings were classified as "affected". When these subjects were classified as "unknown" the maximum LOD scores ranged from 2.99 to 3.25 (theta = 0.00). The results suggest that in this population genetic predisposition to MS is closely linked to the MBP gene and that polymorphism at the MBP locus or an adjacent locus has a role in the aetiology of MS.

    Lancet (London, England) 1992;340;8826;987-91

  • DNA length polymorphism 5' to the myelin basic protein gene is associated with multiple sclerosis.

    Boylan KB, Takahashi N, Paty DW, Sadovnick AD, Diamond M, Hood LE and Prusiner SB

    Department of Neurology, University of California, San Francisco 94143-0518.

    A site of DNA polymorphism linked to the myelin basic protein gene, identified as restriction fragment length polymorphism, was analyzed in a population-based study comparing patients with clinically definite multiple sclerosis (MS) and population-matched control subjects. A 0.9-kilobase (kb) genomic DNA fragment (EcoG) encompassing the first exon of the human myelin basic protein gene, located on the long arm of chromosome 18, identified ten alleles arising from a region of DNA, 1.5 kb 5' to the myelin basic protein gene first exon coding region. Produced by RsaI digests and ranging in length from 2.05 to 2.15 kb, these alleles vary in size by up to 100 base pairs due to insertion or deletion, or both, from a 1-kb length of repetitive DNA. Allele frequencies among 65 patients with MS were compared with those of 63 control subjects. Chi square for these data was significant (p less than 0.001), largely due to a preponderance in the patients with MS of alleles in the 2.14- to 2.15-kb range. Comparison of the numbers of patients with MS and control subjects bearing specific alleles showed that 45% of the patients carried at least one allele of 2.14 to 2.15 kb as opposed to 19% of control subjects (p less than 0.005). These data, while preliminary, suggest that patients with MS differ from population-matched control subjects with respect to DNA polymorphism linked to the myelin basic protein gene. Although no pathogenic relationship between this polymorphism and MS can be presupposed, this finding raises the possibility that the myelin basic protein gene or some other myelin basic protein-linked locus may be a factor in susceptibility to MS.

    Funded by: NINDS NIH HHS: NS 14069

    Annals of neurology 1990;27;3;291-7

Literature (16)

Pubmed - human_disease

  • Investigation of a neuronal nitric oxide synthase gene (NOS1) polymorphism in a multiple sclerosis population.

    Tajouri L, Ferreira L, Ovcaric M, Curtain R, Lea R, Csurhes P, Pender MP and Griffiths LR

    Genomics Research Centre, School of Health Science, Griffith University Gold Coast, Southport, Queensland, 4215 Australia.

    Multiple Sclerosis (MS) is a chronic neurological disease characterized by demyelination associated with infiltrating white blood cells in the central nervous system (CNS). Nitric oxide synthases (NOS) are a family of enzymes that control the production of nitric oxide. It is possible that neuronal NOS could be involved in MS pathophysiology and hence the nNOS gene is a potential candidate for involvement in disease susceptibility. The aim of this study was to determine whether allelic variation at the nNOS gene locus is associated with MS in an Australian cohort. DNA samples obtained from a Caucasian Australian population affected with MS and an unaffected control population, matched for gender, age and ethnicity, were genotyped for a microsatellite polymorphism in the promoter region of the nNOS gene. Allele frequencies were compared using chi-squared based statistical analyses with significance tested by Monte Carlo simulation. Allelic analysis of MS cases and controls produced a chi-squared value of 5.63 with simulated P = 0.96 (OR(max) = 1.41, 95% CI: 0.926-2.15). Similarly, a Mann-Whitney U analysis gave a non-significant P-value of 0.377 for allele distribution. No differences in allele frequencies were observed for gender or clinical course subtype (P > 0.05). Statistical analysis indicated that there is no association of this nNOS variant and MS and hence the gene does not appear to play a genetically significant role in disease susceptibility.

    Journal of the neurological sciences 2004;218;1-2;25-8

  • Myelin basic protein gene is associated with MS in DR4- and DR5-positive Italians and Russians.

    Guerini FR, Ferrante P, Losciale L, Caputo D, Lombardi ML, Pirozzi G, Luongo V, Sudomoina MA, Andreewski TV, Alekseenkov AD, Boiko AN, Gusev EI and Favorova OO

    Laboratory of Biology, Don C. Gnocchi Foundation, ONLUS, IRCCS, Italy.

    Background: The myelin basic protein (MBP) gene may confer genetic susceptibility to multiple sclerosis (MS). The association of MS with alleles of the (TGGA)n variable number tandem repeat (VNTR) 5' to the MBP gene is the subject of conflicting reports.

    Objective: To study possible MS association with VNTR alleles of MBP gene in ethnic Italians and ethnic Russians.

    Methods: Two hundred sixty-nine unrelated patients with definite MS and 385 unrelated healthy control subjects from Italy and Russia were genotyped for the MBP VNTR region and for the human leukocyte antigen (HLA) class II DRB1 gene. The phenotype, allele, and genotype frequencies for two groups of MBP alleles were determined. Patients and control subjects were stratified according to HLA-DRB1 phenotypes.

    Results: The distribution of MBP alleles and genotypes in the two ethnic groups, including both MS patients and control subjects, was very similar. When MS patients and healthy control subjects were stratified according to HLA-DRB1 phenotypes, a significant association of MS with MBP alleles was found only in the DR4- and DR5-positive subgroups. A significant association with MBP alleles was also observed in the nonstratified groups, owing mainly to the contribution of the DR4- and DR5-positive individuals.

    Conclusion: Polymorphism of the MBP or another gene in its vicinity appears to contribute to the etiology of MS for the subgroups of DR4- and DR5-positive Italians and Russians.

    Neurology 2003;61;4;520-6

  • A polymorphism in the repetitive (TGGA)n sequence 5' to the human myelin basic protein gene in Italian multiple sclerosis patients.

    Guerini FR, Losciale L, Mediati M, Speciale L, Mancuso R, Saresella M, Calvo MG, Caputo D and Ferrante P

    Laboratory of Biology, Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.

    Human myelin basic protein (hMBP) gene is one of the candidate genes in the complex mosaic of multiple sclerosis (MS) susceptibility. In this study we verified the distribution of the polymorphism of the region 5' flanking the first exon of the hMBP gene, in 97 relapsing remitting, 74 primary progressive Italian MS patients, and in 236 healthy controls, using polymerase chain reaction (PCR) and gel electrophoresis analysis in this region from 1116 - 1540 nt. Three different band patterns were observed: one homozygote with a 354 bp long fragment, one homozygote with 424 bp long fragment and one heterozygote with both bands present. The short fragment was statistically more frequent in RRMS patients than in HC (P<0.05). The long fragment was more present in HC. Similarly the short homozygous pattern (354 bp/354 bp) was significantly higher in the RRMS patients versus the healthy controls (P<0.01). The sequence analysis of the hMBP alleles showed that while the long fragments matched the prototype sequence completely, all the short fragments showed a deletion of 70 bp from nt 1177 to nt 1247, which explains the short 354 bp allele detected by PCR. Moreover two single mismatches in positions 1386 (T-->C) and 1431 (G-->A), were present only in the short hMBP fragment.

    Journal of neurovirology 2000;6 Suppl 2;S28-32

  • The myelin basic protein gene in multiple sclerosis: identification of discrete alleles of a 1.3 kb tetranucleotide repeat sequence.

    He B, Yang B, Lundahl J, Fredrikson S and Hillert J

    Department of Neurology, NOVUM, Karolinska Institute at Huddinge University Hospital, Sweden.

    Myelin basic protein (MBP) is a potential autoantigen in multiple sclerosis (MS) and its gene therefore is an attractive candidate to confer genetic susceptibility to this disease. Linkage and association with certain alleles of a 1.2 kb tetranucleotide repeat region 5' to the MBP gene with MS have been reported in Finnish patients, and an association has been reported from Denmark. However, these findings have not been confirmed in subsequent analyses in other populations. A limitation of previous studies has been the low resolution of the typing procedure. We have investigated the same polymorphism in thirty-four Swedish nuclear families with 2 or 3 MS patients. and in 149 unrelated Swedish MS patients and 95 healthy controls using a fluorescence-based semi-automated technique which allowed the identification of discrete tetrarepeat numbers. Neither parametric two-point linkage analysis nor a nonparametric affected pedigree members analysis showed any sign of linkage. In addition, the distribution of alleles was similar in patients and controls. We conclude that the MBP gene does not influence susceptibility to MS in Swedish patients.

    Acta neurologica Scandinavica 1998;97;1;46-51

  • Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences.

    Price SE, Sharpe G, Boots A, Poutsma A, Mason C, James J, Hinks L and Thompson RJ

    Wessex Human Genetics Institute, Southampton General Hospital, UK.

    Susceptibility to multiple sclerosis (MS) is widely held to have a strong genetic component. While the identities of genes conferring susceptibility are currently unknown, possible candidates include those genes coding for proteins which function in central nervous system (CNS) myelin. Two such genes are the human myelin basic protein (MBP) and proteolipid protein (PLP) genes, whose products make up approximately 80% of the total protein in CNS myelin. The association of a variable number tandem repeat (VNTR) 5' to the human MBP gene with MS has been the subject of conflicting reports. Here we test the hypothesis that mutations in the human MBP and PLP genes might be associated with MS by examining the entire expressed sequence of both genes by single strand conformation polymorphism (SSCP) analysis, using a panel of 71 MS patients and 71 controls. We have also re-examined the VNTR region in patients and controls. Three base changes were found in the human PLP gene and nine base changes in the human MBP gene; these were essentially equally distributed between patients and controls. No preferential distribution of various alleles of the VNTR between patients and controls was found. Although intronic and regulatory regions have not been examined, it would appear unlikely that mutations in these genes coding for the two major CNS myelin proteins contribute significantly to genetic susceptibility to MS.

    Neuropathology and applied neurobiology 1997;23;6;457-67

  • A repetitive DNA sequence 5' to the human myelin basic protein gene may be linked to MS in Danes.

    Ibsen SN and Clausen J

    Department for Life Sciences and Chemistry, Roskilde University, Denmark.

    The myelin basic protein (MBP) gene is a candidate locus for disease susceptibility in multiple sclerosis (MS). In the present study a part of the tetranucleotide (TGGA)n repeat polymorphism 5' to the MBP gene was examined in 90 Danish MS patients and 106 controls. Lymphocyte DNA was isolated and used in PCR assay. The PCR fragments produced were separated by agarose and acrylamide electrophoresis. Hereby we found three different bandpatterns i.e. a homozygote with a 450 bp fragment, a homozygote with a fragment 375 bp and a heterozygote with both bands present. The 450 bp fragment occurred significantly more often among MS than in the control group and the 375 bp fragment was underrepresented among MS than in the control group. The differences between incidence of the three band pattern in the MS and the control group were significant different at 1% level. Our study thus indicate that there is an association between MS and a length polymorphism of the 5' end to the MBP gene in Danish MS patients.

    Acta neurologica Scandinavica 1996;93;4;236-40

  • PCR typing of two short tandem repeat (STR) structures upstreams of the human myelin basic protein (MBP) gene; the genetic susceptibility in multiple sclerosis and monosymptomatic idiopathic optic neuritis in Danes.

    Nellemann LJ, Frederiksen J and Morling N

    Department of Forensic Genetics, University of Copenhagen, Denmark.

    We investigated two short tandem tetranucleotide (TGGA) repeat polymorphisms upstreams of the myelin basic protein (MBP) gene. The region was amplified by the polymerase chain reaction (PCR) and the two repeat systems were separated by cutting with the restriction enzyme NlaIII. The lengths of the DNA fragments were analyzed by vertical electrophoresis in polyacrylamide gels followed by silver staining. We compared the DNA fragment frequencies of the two MBP regions in 34 patients suffering from multiple sclerosis and in 78 suffering from monosymptomatic idiopathic optic neuritis to those in 200 healthy controls. We found no significant differences between the MBP fragment frequencies in either of the patient groups and in the control group.

    Multiple sclerosis (Houndmills, Basingstoke, England) 1995;1;3;186-9

  • Genetic susceptibility to multiple sclerosis may be linked to polymorphism of the myelin basic protein gene.

    Ibsen SN and Clausen J

    Department for Life Sciences and Chemistry, Roskilde University, Denmark.

    The present paper compares the genetic polymorphism of a part of the myelin basic protein (MBP) gene in 64 Danish MS patients with that of 57 normal controls. PCR analysis, using primers flanking the 5' area from 479 to 1812 bp upstream the initiator methionine in the MBP gene, revealed that genetic susceptibility to MS is linked to polymorphism in the part of the MBP gene studied. Thus we found three different band patterns i.e. a homozygote with a 1445 bp long fragment, a homozygote with a fragment 1318 bp long and a heterozygote with both bands present. 59% of 64 patients with MS were homozygous for 1.445 kb allele, versus 40% of 57 control subjects, 18% of the control subjects were homozygous for the 1.318 kb, while only 0.7% of the MS patients possessed this allele. The differences between incidence of the three band pattern in the MS and the control group were significant at 1% level. Validation analysis furthermore support, the view that the 1445 bp PCR fragment is associated with MS.

    Journal of the neurological sciences 1995;131;1;96-8

  • The myelin basic protein gene is not a major susceptibility locus for multiple sclerosis in Italian patients.

    Eoli M, Pandolfo M, Milanese C, Gasparini P, Salmaggi A and Zeviani M

    2nd Division of Neurology, Istituto Nazionale Neurologico C. Besta, Milan, Italy.

    To verify whether multiallelic polymorphism adjacent to the gene encoding for myelin basic protein is associated with or linked to multiple sclerosis in Italians, we studied 54 sporadic patients, 55 control subjects and 18 families with two or more affected individuals. Allelic typing was carried out by analysis of fragment length polymorphisms after DNA amplification by the polymerase chain reaction. The presence of linkage with the disease was tested according to either autosomal dominant or autosomal recessive modes of inheritance, and with or without the introduction of liability classes accounting for the age of the individuals. Furthermore sib-pair analysis was performed in 11 siblings. No evidence for association or linkage between the myelin basic protein gene polymorphism and multiple sclerosis was found. Our data indicate that in the Italian population the myelin basic protein gene does not play a major role in conferring genetic susceptibility to multiple sclerosis, and suggest that the latter is a heterogeneous phenomenon, possibly influenced by the different ethnic origin of the populations which have been investigated.

    Journal of neurology 1994;241;10;615-9

  • No linkage or association between multiple sclerosis and the myelin basic protein gene in affected sibling pairs.

    Wood NW, Holmans P, Clayton D, Robertson N and Compston DA

    University of Cambridge Neurology unit, Addenbrooke's Hospital, UK.

    Myelin basic protein was examined as a candidate gene for susceptibility to multiple sclerosis using two adjacent amplification fragment length polymorphisms (AmpFLPs), containing seven and six highly informative alleles respectively. No allelic association was found with multiple sclerosis, comparing 77 cases and 88 controls, and there was no evidence for linkage in 73 affected sibling pairs, using the methods of identity by descent and identity by state.

    Journal of neurology, neurosurgery, and psychiatry 1994;57;10;1191-4

  • Myelin basic protein gene polymorphism is not associated with chronic progressive multiple sclerosis.

    Vandevyver C, Stinissen P, Cassiman JJ and Raus J

    Department of Immunology/Biotechnology, Dr. L. Willems-Instituut at Diepenbeek, Belgium.

    In the present study a tetranucleotide (TGGA)n repeat polymorphism 5' to the myelin basic protein (MBP) gene was evaluated in a group of HLA-class II-typed, chronic progressive multiple sclerosis (MS) patients. This polymorphism has been reported by others to be associated with MS. Contrary to these reports we observed similar allele frequencies in patients and controls. Our results indicate that there is no association between MS and a polymorphism 5' to the MBP gene.

    Journal of neuroimmunology 1994;52;1;97-9

  • Identification of a new polymorphism in the human proteolipid protein gene.

    Poduslo SE, Decker P, Astle H, Kurth J and LaBate M

    Department of Neurology, Texas Tech University Health Sciences Center, Lubbock 79430.

    A polymorphism in the gene for proteolipid protein has been identified, using amplification by the polymerase chain reaction, restriction enzyme digestion, and fragment separation by polyacrylamide gel electrophoresis. The polymorphism is located in the transcribed 3'-untranslated region, a region with potential regulatory signals. The mutation consists of a single base pair insertion into a Hae III restriction site, producing a larger rare fragment of 409 bp as compared with the more frequent 325 bp fragment. The gene for proteolipid protein is on the X chromosome; thus the males are hemizygous for the rare allele and the females are heterozygous carriers. The polymorphism occurs with a frequency of 0.046 in a population of European origin and also has a rare frequency in multiple sclerosis patients.

    Neurochemistry international 1993;23;5;413-7

  • Lack of association between myelin basic protein gene microsatellite and multiple sclerosis.

    Graham CA, Kirk CW, Nevin NC, Droogan AG, Hawkins SA, McMillan SA and McNeill TA

    Lancet (London, England) 1993;341;8860;1596

  • Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene.

    Tienari PJ, Wikström J, Sajantila A, Palo J and Peltonen L

    Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.

    Genetic factors have been implicated in the aetiology of multiple sclerosis (MS), but the genes conferring susceptibility to MS have not been identified. We carried out genetic linkage and association analyses by studying polymorphism of the myelin basic protein (MBP) gene on chromosome 18, a candidate gene for MS, in 21 MS families, 51 additional unrelated patients with definite MS, and 85 controls. All subjects were Finnish, and 14 of the families were from an area with an exceptional familial clustering of MS. Magnetic resonance imaging (MRI) was used to examine subclinical disease in symptom-free family members. In the association analysis, the allele frequencies between MS patients and controls differed significantly, p = 0.000049), the difference being attributable mainly to a higher frequency of a 1.27 kb allele among patients. In the linkage analysis, based on an autosomal dominant model and penetrance 0.05, a maximum LOD score of 3.42 (theta = 0.00) was obtained when patients with optic neuritis and their symptom-free siblings with abnormal MRI findings were classified as "affected". When these subjects were classified as "unknown" the maximum LOD scores ranged from 2.99 to 3.25 (theta = 0.00). The results suggest that in this population genetic predisposition to MS is closely linked to the MBP gene and that polymorphism at the MBP locus or an adjacent locus has a role in the aetiology of MS.

    Lancet (London, England) 1992;340;8826;987-91

  • DNA length polymorphism 5' to the myelin basic protein gene is associated with multiple sclerosis.

    Boylan KB, Takahashi N, Paty DW, Sadovnick AD, Diamond M, Hood LE and Prusiner SB

    Department of Neurology, University of California, San Francisco 94143-0518.

    A site of DNA polymorphism linked to the myelin basic protein gene, identified as restriction fragment length polymorphism, was analyzed in a population-based study comparing patients with clinically definite multiple sclerosis (MS) and population-matched control subjects. A 0.9-kilobase (kb) genomic DNA fragment (EcoG) encompassing the first exon of the human myelin basic protein gene, located on the long arm of chromosome 18, identified ten alleles arising from a region of DNA, 1.5 kb 5' to the myelin basic protein gene first exon coding region. Produced by RsaI digests and ranging in length from 2.05 to 2.15 kb, these alleles vary in size by up to 100 base pairs due to insertion or deletion, or both, from a 1-kb length of repetitive DNA. Allele frequencies among 65 patients with MS were compared with those of 63 control subjects. Chi square for these data was significant (p less than 0.001), largely due to a preponderance in the patients with MS of alleles in the 2.14- to 2.15-kb range. Comparison of the numbers of patients with MS and control subjects bearing specific alleles showed that 45% of the patients carried at least one allele of 2.14 to 2.15 kb as opposed to 19% of control subjects (p less than 0.005). These data, while preliminary, suggest that patients with MS differ from population-matched control subjects with respect to DNA polymorphism linked to the myelin basic protein gene. Although no pathogenic relationship between this polymorphism and MS can be presupposed, this finding raises the possibility that the myelin basic protein gene or some other myelin basic protein-linked locus may be a factor in susceptibility to MS.

    Funded by: NINDS NIH HHS: NS 14069

    Annals of neurology 1990;27;3;291-7

Pubmed - other

  • Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation.

    Warshawsky I, Rudick RA, Staugaitis SM and Natowicz MR

    Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

    We report a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and cerebrospinal fluid immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis and whose son died at age 10 years of an unknown congenital neurodevelopmental disorder. Sequencing of the proteolipid protein 1 gene showed a novel mutation, Leu30Arg (c.89TG), in the mother and son. Pelizaeus-Merzbacher disease is the cause of death in the son and explains the mother's adult-onset neurological disorder. This case goes against dogma that mothers of severely affected sons are asymptomatic as adults and expands the differential diagnosis of primary progressive multiple sclerosis to include proteolipid protein 1 gene mutations.

    Annals of neurology 2005;58;3;470-3

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EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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