G2Cdb::Human Disease report

Disease id
D00000217
Name
X-linked hydrocephalus
Nervous system disease
yes

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001881 L1CAM
L1 cell adhesion molecule
Y (1303258) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (7762552) Unknown (?) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (7881431) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8069317) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8728703) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8741350) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8786080) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8929944) Frameshift mutation (FS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8929944) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8929944) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9088116) Unknown (?) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9195224) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9195224) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9195224) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9195224) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9195224) Frameshift mutation (FS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9268105) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9268105) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9268105) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9279760) Unknown (?) ?
G00001881 L1CAM
L1 cell adhesion molecule
Y (9440802) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9452098) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9521424) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9521424) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9643285) Single nucleotide polymorphism (SNP) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (10797421) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (10797421) Frameshift mutation (FS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (10797421) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (12435569) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (12725590) Unknown (?) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (15108295) Single nucleotide polymorphism (SNP) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (15108295) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (15108295) Insertion (I) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (15148591) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (15148591) Nonsense (No) Y

References

  • Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

    Hübner CA, Utermann B, Tinschert S, Krüger G, Ressler B, Steglich C, Schinzel A and Gal A

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

    L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

    Human mutation 2004;23;5;526

  • Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM.

    Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y and Yamasaki M

    Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan. okamoto@osaka.email.ne.jp.

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural-cell adhesion molecules, are associated with X-linked hydrocephalus and some allelic disorders. Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. There have been three reports of patients with X-linked hydrocephalus and HSCR with a mutation in the L1CAM gene. We report three more patients with similar conditions. We suspect that decreased L1CAM may be a modifying factor in the development of HSCR.

    Journal of human genetics 2004;49;6;334-337

  • X-linked hydrocephalus: another two families with an L1 mutation.

    Rodríguez Criado G, Pérez Aytés A, Martínez F, Vos YJ, Verlind E, González-Meneses López A, Gómez de Terreros Sánchez I and Schrander-Stumpel C

    Unidad de Dismorfología, H.I.U.V. Rocío, Sevilla, Spain.

    X-linked hydrocephalus is a variable condition caused by mutations in the gene encoding for L1CAM. This gene is located at Xq28. Clinically the spectrum ranges from males with lethal congenital hydrocephalus to mild/moderate mental retardation and spastic paraplegia. Few carrier females show minimal signs of the syndrome. Although most cases are familial, de novo situations have been reported. We report two new families with the syndrome and a L1 mutation. Family 1 has two patients and family 2 a single patient. Clinical diagnosis in all three affected boys was beyond doubt. Prenatal testing through chorionic villus biopsy is possible only with a demonstrated L1 mutation. In lethal sporadic cases neuropathology is very important in order to evaluate for features of the syndrome. We stress the importance of further clinical reports including data on neuropathology and DNA analysis in order to further understand the mechanisms involved in this disorder.

    Genetic counseling (Geneva, Switzerland) 2003;14;1;57-65

  • X-linked hydrocephalus: a novel missense mutation in the L1CAM gene.

    Sztriha L, Vos YJ, Verlind E, Johansen J and Berg B

    Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain.

    X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small gyri, hypoplasia of the white matter, agenesis of the corpus callosum, and lack of cleavage of the thalami. Scanning the L1 neuronal cell adhesion molecule gene in Xq28 revealed a novel missense mutation: transition of a guanine to cytosine at position 1,243, which led to conversion of alanine to proline at position 415 in the Ig 4 domain of the L1 protein. It is likely that the X-linked hydrocephalus and cerebral dysgenesis are a result of the abnormal structure and function of the mutant L1 protein.

    Pediatric neurology 2002;27;4;293-6

  • Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease.

    Finckh U, Schröder J, Ressler B, Veske A and Gal A

    Department of Human Genetics, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany.

    Mutations in L1CAM, the gene encoding the L1 neuronal cell adhesion molecule, lead to an X-linked trait characterized by one or more of the symptoms of hydrocephalus, adducted thumbs, agenesis or hypoplasia of corpus callosum, spastic paraplegia, and mental retardation (L1-disease). We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory elements in the 5'-untranslated region of the gene. Forty-six pathogenic mutations were found (30.1% detection rate), the majority consisting of nonsense, frameshift, and splice site mutations. In eight cases, segregation analysis disclosed recent de novo mutations. Statistical analysis of the data indicates a significant effect on mutation detection rate of (i) family history, (ii) number of L1-disease typical clinical findings, and (iii) presence or absence of signs not typically associated with L1CAM-disease. Whereas mutation detection rate was 74.2% for patients with at least two additional cases in the family, only 16 mutations were found in the 102 cases with negative family history (15.7% detection rate). Our data suggest a higher than previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus.

    American journal of medical genetics 2000;92;1;40-6

  • A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS).

    Du YZ, Dickerson C, Aylsworth AS and Schwartz CE

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA.

    The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in the development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC). In an analysis of a family with HSAS, we identified a C-->T transition (C924T) in exon 8 that was initially thought to have no effect on the protein sequence as the alteration affected the third base of a codon (G308G). Extensive analysis of the other 27 exons showed no other alteration. A review of the sequence surrounding position 924 indicated that the C-->T transition created a potential 5' splice site consensus sequence, which would result in an in frame deletion of 69 bp from exon 8 and 23 amino acids of the L1CAM protein. RT-PCR of the RNA from an affected male fetus and subsequent sequence analysis confirmed the use of the new splice site. This is the first report of a silent nucleotide substitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more important role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.

    Journal of medical genetics 1998;35;6;456-62

  • Hydrocephalus and spastic paraplegia result from a donor splice site mutation (2872 + 1G to A) in the L1CAM gene in a Venezuelan pedigree.

    Claes S, Aguirre T, Simosa V, Bustos T, Lander R, Piras M, Legius E, Cassiman JJ and Raeymaekers P

    Center for Human Genetics, University of Leuven, Belgium.

    Human mutation 1998;Suppl 1;S240-1

  • Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene.

    Du YZ, Srivastava AK and Schwartz CE

    J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, South Carolina 29646, USA.

    Restriction endonuclease fingerprinting (REF) has been utilized to screen 19 of the 28 exons in the L1CAM gene using only 5 PCR reactions. The clustered exons were amplified and the PCR products were subjected to endonuclease digestion and subsequent gel electrophoresis to produce a highly informative fingerprint for each PCR product. An alteration in the fingerprint, when compared to a control, determined the specific DNA fragment containing the mutation. Sequencing of the corresponding exon and flanking region was done to determine the precise location of the mutation. Using this method we have identified 6 novel mutations in the L1CAM gene in 5 patients with X-linked hydrocephalus and 2 patients with MASA. One of the mutations was common to both a patient with HSAS and a patient with MASA. The utilization of REF will allow for easier and quicker detection of mutations in the L1CAM gene. This method should be applicable for screening other genes with multiple, clustered exons.

    Human mutation 1998;11;3;222-30

  • L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling.

    Takahashi S, Makita Y, Okamoto N, Miyamoto A and Oki J

    Department of Pediatrics, Asahikawa Medical College, Nishikagura, Japan.

    Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.

    Brain & development 1997;19;8;559-62

  • Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

    Gu SM, Orth U, Zankl M, Schröder J and Gal A

    Institut für Humangenetik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.

    Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

    American journal of medical genetics 1997;71;3;336-40

  • Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM.

    Okamoto N, Wada Y and Goto M

    Department of Planning and Research, Osaka Medical Centre, Japan.

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural cell adhesion molecules, are associated with X linked hydrocephalus and some allelic disorders. We describe a patient with X linked hydrocephalus and Hirschsprung's disease (HSCR) with a novel mutation in the L1CAM gene. This is the first report of HSCR with a mutant neural cell adhesion molecule. Although the disease phenotypes of this patient may well be independent, the alternative explanation that L1CAM mutations may contribute to both phenotypes cannot be excluded in view of an earlier report on another patient with both X linked hydrocephalus and HSCR.

    Journal of medical genetics 1997;34;8;670-1

  • Nine novel L1 CAM mutations in families with X-linked hydrocephalus.

    MacFarlane JR, Du JS, Pepys ME, Ramsden S, Donnai D, Charlton R, Garrett C, Tolmie J, Yates JR, Berry C, Goudie D, Moncla A, Lunt P, Hodgson S, Jouet M and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

    Mutations in the gene for neural cell adhesion molecule L1 are responsible for the highly variable phenotype found in families with X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I. To date, 32 different mutations have been observed, the majority being unique to individual families. Here, we report nine novel mutations in L1 in 10 X-linked hydrocephalus families. Four mutations truncate the L1 protein and eliminate cell surface expression, and two would produce abnormal L1 through alteration of RNA processing. A further two of these mutations are small in-frame deletions that have occurred through a mechanism involving tandem repeated sequences. Together with a single missense mutation, these latter examples contribute to the growing number of existing mutations that affect short regions of the L1 protein that may have particular functional significance.

    Human mutation 1997;9;6;512-8

  • A novel mutation in L1CAM gene in a Japanese patient with X-linked hydrocephalus.

    Okamoto N, Wada Y, Kawabata H, Ishikiriyama S and Takahashi S

    Department of Planning and Research, Osaka Medical Center, Japan.

    L1CAM is a member of the immunoglobulin gene superfamily of neural adhesion molecule. Abnormality of the L1CAM gene is associated with X-linked recessive form of congenital hydrocephalus (HSAS; hydrocephalus due to congenital stenosis of aqueduct of Sylvius) and some allelic disorders. Four new patients with congenital hydrocephalus consistent with the X-linked type were described. One of them had a novel mutation in the L1CAM gene.

    The Japanese journal of human genetics 1996;41;4;431-7

  • A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus.

    Takechi T, Tohyama J, Kurashige T, Maruta K, Uyemura K, Ohi T, Matsukura S and Sakuragawa N

    Department of Inherited Metabolic Disease, National Institute of Neuroscience, Tokyo, Japan.

    X-linked hydrocephalus (HSAS) is the most common form of inherited hydrocephalus characterized by hydrocephalus due to stenosis of the aqueduct of Sylvius, mental retardation, clasped thumbs, and spastic paraparesis. MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs. Linkage analysis studies implicated the neural cell adhesion molecule L1 (L1CAM) gene as a candidate gene for these X-linked disorders. This genetic study analyzes the L1CAM gene in a Japanese family with members suffering from HSAS, and describes a deletion of five nucleotides in exon 8. Screening by Bg1I digestion of polymerase chain reaction (PCR) products revealed that two siblings have the same mutation and a sister was identified as a heterozygous carrier. The 5 nucleotide deletion causes a shift of the reading frame and introduces a premature stop codon 72 nucleotides downstream, which might result in a truncated protein. The mutation identified herein is a novel L1CAM mutation, which triggers hydrocephalus. We report a unique L1CAM mutation that causes HSAS: the first report of such a mutation in a Japanese family.

    Human genetics 1996;97;3;353-6

  • [A family with X-linked hydrocephalus resulting from mutations in the neural cell adhesion molecule L1].

    Maruta K, Ohi T, Ohdo S, Takechi T, Sakuragawa N and Matsukura S

    Division of Neurology, National Nichinan Hospital, Miyazaki, Japan.

    We present the two siblings with X-linked hydrocephalus (XLH) and discuss the clinical features and genetical analysis of them. Case 1. The proband, a male, was delivered by the emergency cesarean section because of enlarged head circumference (44cm). His head circumference at 24 years old was 92cm. Neurological examination revealed adducted thumbs, horizontal nystagmus, hyperreflexia and spasticity of legs. He had tonic convulsions. MRI revealed a very thin layer of cerebral cortex. Molecular analysis revealed a deletion of 5 bases in exon 8 of the cell adhesion molecule L1 (L1CAM) gene located at chromosome Xq28. Case 2. The younger maternal half brother of case 1 was also born by the cesarean section, with 48cm in head circumference. A ventriculoatrial shunt was placed at the first month old. Epileptic seizures were seen. At the age of 21 years he had a head circumference of 59cm. A physical examination showed bilateral adducted thumbs, upward deviation of eyes, hyperreflexia and spasticity of legs. CT showed marked generalized ventricular enlargement including the fourth ventricle. Molecular analysis confirmed the same mutations as that of case 1. A maternal uncle had a previous diagnosis of hydrocephalus, and a sister is identified as a heterozygous carrier from molecular genetical analysis. Our results indicate that HLX is caused by the mutations in the gene for neural L1CAM in our family.

    Rinsho shinkeigaku = Clinical neurology 1996;36;3;462-6

  • Discordant segregation of Xq28 markers and a mutation in the L1 gene in a family with X linked hydrocephalus.

    Jouet M, Strain L, Bonthron D and Kenwrick S

    Department of Medicine, University of Cambridge, UK.

    X linked recessive hydrocephalus is the most common hereditary form of hydrocephalus. Genetic analysis indicates that the majority of cases are caused by mutations in a single gene in Xq28, recently identified as the gene for neural cell adhesion molecule L1. Genetic heterogeneity for this disorder was suggested following the description of a single large pedigree where X linked hydrocephalus showed lack of linkage to Xq28 markers flanking the L1 gene. Mutation analysis in this family shows a single base pair deletion within the coding sequence of the L1 gene that would result in truncation of the mature protein. The nature of the mutation and its segregation with the disease through the pedigree indicate that it is the cause of X linked hydrocephalus in this family. These results are at odds with data obtained through segregation of alleles for markers flanking the L1 gene. Somatic and germline mosaicism is the most plausible explanation for these data, which also provide further evidence for genetic homogeneity of X linked hydrocephalus.

    Journal of medical genetics 1996;33;3;248-50

  • Five novel mutations in the L1CAM gene in families with X linked hydrocephalus.

    Gu SM, Orth U, Veske A, Enders H, Klunder K, Schlosser M, Engel W, Schwinger E and Gal A

    Institut fur Humangenetik, Medizinische Universitat zu Lubeck, Germany.

    Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence of L1CAM at the cell surface. The two missense mutations (Tyr194Cys and Pro240Leu) may considerably alter the structure of the L1CAM protein. These data provide convincing evidence that XHC is genetically extremely heterogeneous.

    Journal of medical genetics 1996;33;2;103-6

  • New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

    Jouet M, Moncla A, Paterson J, McKeown C, Fryer A, Carpenter N, Holmberg E, Wadelius C and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, United Kingdom.

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

    American journal of human genetics 1995;56;6;1304-14

  • X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene.

    Fransen E, Schrander-Stumpel C, Vits L, Coucke P, Van Camp G and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;12;2255-6

  • Identification of a 5' splice site mutation in intron 4 of the L1CAM gene in an X-linked hydrocephalus family.

    Coucke P, Vits L, Van Camp G, Serville F, Lyonnet S, Kenwrick S, Rosenthal A, Wehnert M, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;4;671-3

  • Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus.

    Rosenthal A, Jouet M and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    A locus for X-linked hydrocephalus (HSAS), which is characterized by mental retardation and enlarged brain ventricles, maps to the same subchromosomal region (Xq28) as the gene for neural cell adhesion molecule L1. We have found novel L1 mRNA species in cells from affected members of a HSAS family containing deletions and insertions produced by the utilization of alternative 3' splice sites. A point mutation at a potential branch point signal in an intron segregates with the disease and is likely to be responsible for the abnormal RNA processing. These results suggest that HSAS is a disorder of neuronal cell migration due to disruption of L1 protein function.

    Nature genetics 1992;2;2;107-12

Literature (21)

Pubmed - human_disease

  • Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

    Hübner CA, Utermann B, Tinschert S, Krüger G, Ressler B, Steglich C, Schinzel A and Gal A

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

    L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

    Human mutation 2004;23;5;526

  • A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS).

    Du YZ, Dickerson C, Aylsworth AS and Schwartz CE

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA.

    The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in the development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC). In an analysis of a family with HSAS, we identified a C-->T transition (C924T) in exon 8 that was initially thought to have no effect on the protein sequence as the alteration affected the third base of a codon (G308G). Extensive analysis of the other 27 exons showed no other alteration. A review of the sequence surrounding position 924 indicated that the C-->T transition created a potential 5' splice site consensus sequence, which would result in an in frame deletion of 69 bp from exon 8 and 23 amino acids of the L1CAM protein. RT-PCR of the RNA from an affected male fetus and subsequent sequence analysis confirmed the use of the new splice site. This is the first report of a silent nucleotide substitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more important role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.

    Journal of medical genetics 1998;35;6;456-62

  • Hydrocephalus and spastic paraplegia result from a donor splice site mutation (2872 + 1G to A) in the L1CAM gene in a Venezuelan pedigree.

    Claes S, Aguirre T, Simosa V, Bustos T, Lander R, Piras M, Legius E, Cassiman JJ and Raeymaekers P

    Center for Human Genetics, University of Leuven, Belgium.

    Human mutation 1998;Suppl 1;S240-1

  • L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling.

    Takahashi S, Makita Y, Okamoto N, Miyamoto A and Oki J

    Department of Pediatrics, Asahikawa Medical College, Nishikagura, Japan.

    Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.

    Brain & development 1997;19;8;559-62

  • Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM.

    Okamoto N, Wada Y and Goto M

    Department of Planning and Research, Osaka Medical Centre, Japan.

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural cell adhesion molecules, are associated with X linked hydrocephalus and some allelic disorders. We describe a patient with X linked hydrocephalus and Hirschsprung's disease (HSCR) with a novel mutation in the L1CAM gene. This is the first report of HSCR with a mutant neural cell adhesion molecule. Although the disease phenotypes of this patient may well be independent, the alternative explanation that L1CAM mutations may contribute to both phenotypes cannot be excluded in view of an earlier report on another patient with both X linked hydrocephalus and HSCR.

    Journal of medical genetics 1997;34;8;670-1

  • A novel mutation in L1CAM gene in a Japanese patient with X-linked hydrocephalus.

    Okamoto N, Wada Y, Kawabata H, Ishikiriyama S and Takahashi S

    Department of Planning and Research, Osaka Medical Center, Japan.

    L1CAM is a member of the immunoglobulin gene superfamily of neural adhesion molecule. Abnormality of the L1CAM gene is associated with X-linked recessive form of congenital hydrocephalus (HSAS; hydrocephalus due to congenital stenosis of aqueduct of Sylvius) and some allelic disorders. Four new patients with congenital hydrocephalus consistent with the X-linked type were described. One of them had a novel mutation in the L1CAM gene.

    The Japanese journal of human genetics 1996;41;4;431-7

  • A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus.

    Takechi T, Tohyama J, Kurashige T, Maruta K, Uyemura K, Ohi T, Matsukura S and Sakuragawa N

    Department of Inherited Metabolic Disease, National Institute of Neuroscience, Tokyo, Japan.

    X-linked hydrocephalus (HSAS) is the most common form of inherited hydrocephalus characterized by hydrocephalus due to stenosis of the aqueduct of Sylvius, mental retardation, clasped thumbs, and spastic paraparesis. MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs. Linkage analysis studies implicated the neural cell adhesion molecule L1 (L1CAM) gene as a candidate gene for these X-linked disorders. This genetic study analyzes the L1CAM gene in a Japanese family with members suffering from HSAS, and describes a deletion of five nucleotides in exon 8. Screening by Bg1I digestion of polymerase chain reaction (PCR) products revealed that two siblings have the same mutation and a sister was identified as a heterozygous carrier. The 5 nucleotide deletion causes a shift of the reading frame and introduces a premature stop codon 72 nucleotides downstream, which might result in a truncated protein. The mutation identified herein is a novel L1CAM mutation, which triggers hydrocephalus. We report a unique L1CAM mutation that causes HSAS: the first report of such a mutation in a Japanese family.

    Human genetics 1996;97;3;353-6

  • [A family with X-linked hydrocephalus resulting from mutations in the neural cell adhesion molecule L1].

    Maruta K, Ohi T, Ohdo S, Takechi T, Sakuragawa N and Matsukura S

    Division of Neurology, National Nichinan Hospital, Miyazaki, Japan.

    We present the two siblings with X-linked hydrocephalus (XLH) and discuss the clinical features and genetical analysis of them. Case 1. The proband, a male, was delivered by the emergency cesarean section because of enlarged head circumference (44cm). His head circumference at 24 years old was 92cm. Neurological examination revealed adducted thumbs, horizontal nystagmus, hyperreflexia and spasticity of legs. He had tonic convulsions. MRI revealed a very thin layer of cerebral cortex. Molecular analysis revealed a deletion of 5 bases in exon 8 of the cell adhesion molecule L1 (L1CAM) gene located at chromosome Xq28. Case 2. The younger maternal half brother of case 1 was also born by the cesarean section, with 48cm in head circumference. A ventriculoatrial shunt was placed at the first month old. Epileptic seizures were seen. At the age of 21 years he had a head circumference of 59cm. A physical examination showed bilateral adducted thumbs, upward deviation of eyes, hyperreflexia and spasticity of legs. CT showed marked generalized ventricular enlargement including the fourth ventricle. Molecular analysis confirmed the same mutations as that of case 1. A maternal uncle had a previous diagnosis of hydrocephalus, and a sister is identified as a heterozygous carrier from molecular genetical analysis. Our results indicate that HLX is caused by the mutations in the gene for neural L1CAM in our family.

    Rinsho shinkeigaku = Clinical neurology 1996;36;3;462-6

  • Discordant segregation of Xq28 markers and a mutation in the L1 gene in a family with X linked hydrocephalus.

    Jouet M, Strain L, Bonthron D and Kenwrick S

    Department of Medicine, University of Cambridge, UK.

    X linked recessive hydrocephalus is the most common hereditary form of hydrocephalus. Genetic analysis indicates that the majority of cases are caused by mutations in a single gene in Xq28, recently identified as the gene for neural cell adhesion molecule L1. Genetic heterogeneity for this disorder was suggested following the description of a single large pedigree where X linked hydrocephalus showed lack of linkage to Xq28 markers flanking the L1 gene. Mutation analysis in this family shows a single base pair deletion within the coding sequence of the L1 gene that would result in truncation of the mature protein. The nature of the mutation and its segregation with the disease through the pedigree indicate that it is the cause of X linked hydrocephalus in this family. These results are at odds with data obtained through segregation of alleles for markers flanking the L1 gene. Somatic and germline mosaicism is the most plausible explanation for these data, which also provide further evidence for genetic homogeneity of X linked hydrocephalus.

    Journal of medical genetics 1996;33;3;248-50

  • Identification of a 5' splice site mutation in intron 4 of the L1CAM gene in an X-linked hydrocephalus family.

    Coucke P, Vits L, Van Camp G, Serville F, Lyonnet S, Kenwrick S, Rosenthal A, Wehnert M, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;4;671-3

Pubmed - other

  • Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM.

    Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y and Yamasaki M

    Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan. okamoto@osaka.email.ne.jp.

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural-cell adhesion molecules, are associated with X-linked hydrocephalus and some allelic disorders. Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. There have been three reports of patients with X-linked hydrocephalus and HSCR with a mutation in the L1CAM gene. We report three more patients with similar conditions. We suspect that decreased L1CAM may be a modifying factor in the development of HSCR.

    Journal of human genetics 2004;49;6;334-337

  • X-linked hydrocephalus: another two families with an L1 mutation.

    Rodríguez Criado G, Pérez Aytés A, Martínez F, Vos YJ, Verlind E, González-Meneses López A, Gómez de Terreros Sánchez I and Schrander-Stumpel C

    Unidad de Dismorfología, H.I.U.V. Rocío, Sevilla, Spain.

    X-linked hydrocephalus is a variable condition caused by mutations in the gene encoding for L1CAM. This gene is located at Xq28. Clinically the spectrum ranges from males with lethal congenital hydrocephalus to mild/moderate mental retardation and spastic paraplegia. Few carrier females show minimal signs of the syndrome. Although most cases are familial, de novo situations have been reported. We report two new families with the syndrome and a L1 mutation. Family 1 has two patients and family 2 a single patient. Clinical diagnosis in all three affected boys was beyond doubt. Prenatal testing through chorionic villus biopsy is possible only with a demonstrated L1 mutation. In lethal sporadic cases neuropathology is very important in order to evaluate for features of the syndrome. We stress the importance of further clinical reports including data on neuropathology and DNA analysis in order to further understand the mechanisms involved in this disorder.

    Genetic counseling (Geneva, Switzerland) 2003;14;1;57-65

  • X-linked hydrocephalus: a novel missense mutation in the L1CAM gene.

    Sztriha L, Vos YJ, Verlind E, Johansen J and Berg B

    Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain.

    X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small gyri, hypoplasia of the white matter, agenesis of the corpus callosum, and lack of cleavage of the thalami. Scanning the L1 neuronal cell adhesion molecule gene in Xq28 revealed a novel missense mutation: transition of a guanine to cytosine at position 1,243, which led to conversion of alanine to proline at position 415 in the Ig 4 domain of the L1 protein. It is likely that the X-linked hydrocephalus and cerebral dysgenesis are a result of the abnormal structure and function of the mutant L1 protein.

    Pediatric neurology 2002;27;4;293-6

  • Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease.

    Finckh U, Schröder J, Ressler B, Veske A and Gal A

    Department of Human Genetics, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany.

    Mutations in L1CAM, the gene encoding the L1 neuronal cell adhesion molecule, lead to an X-linked trait characterized by one or more of the symptoms of hydrocephalus, adducted thumbs, agenesis or hypoplasia of corpus callosum, spastic paraplegia, and mental retardation (L1-disease). We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory elements in the 5'-untranslated region of the gene. Forty-six pathogenic mutations were found (30.1% detection rate), the majority consisting of nonsense, frameshift, and splice site mutations. In eight cases, segregation analysis disclosed recent de novo mutations. Statistical analysis of the data indicates a significant effect on mutation detection rate of (i) family history, (ii) number of L1-disease typical clinical findings, and (iii) presence or absence of signs not typically associated with L1CAM-disease. Whereas mutation detection rate was 74.2% for patients with at least two additional cases in the family, only 16 mutations were found in the 102 cases with negative family history (15.7% detection rate). Our data suggest a higher than previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus.

    American journal of medical genetics 2000;92;1;40-6

  • Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene.

    Du YZ, Srivastava AK and Schwartz CE

    J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, South Carolina 29646, USA.

    Restriction endonuclease fingerprinting (REF) has been utilized to screen 19 of the 28 exons in the L1CAM gene using only 5 PCR reactions. The clustered exons were amplified and the PCR products were subjected to endonuclease digestion and subsequent gel electrophoresis to produce a highly informative fingerprint for each PCR product. An alteration in the fingerprint, when compared to a control, determined the specific DNA fragment containing the mutation. Sequencing of the corresponding exon and flanking region was done to determine the precise location of the mutation. Using this method we have identified 6 novel mutations in the L1CAM gene in 5 patients with X-linked hydrocephalus and 2 patients with MASA. One of the mutations was common to both a patient with HSAS and a patient with MASA. The utilization of REF will allow for easier and quicker detection of mutations in the L1CAM gene. This method should be applicable for screening other genes with multiple, clustered exons.

    Human mutation 1998;11;3;222-30

  • Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

    Gu SM, Orth U, Zankl M, Schröder J and Gal A

    Institut für Humangenetik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.

    Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

    American journal of medical genetics 1997;71;3;336-40

  • Nine novel L1 CAM mutations in families with X-linked hydrocephalus.

    MacFarlane JR, Du JS, Pepys ME, Ramsden S, Donnai D, Charlton R, Garrett C, Tolmie J, Yates JR, Berry C, Goudie D, Moncla A, Lunt P, Hodgson S, Jouet M and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

    Mutations in the gene for neural cell adhesion molecule L1 are responsible for the highly variable phenotype found in families with X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I. To date, 32 different mutations have been observed, the majority being unique to individual families. Here, we report nine novel mutations in L1 in 10 X-linked hydrocephalus families. Four mutations truncate the L1 protein and eliminate cell surface expression, and two would produce abnormal L1 through alteration of RNA processing. A further two of these mutations are small in-frame deletions that have occurred through a mechanism involving tandem repeated sequences. Together with a single missense mutation, these latter examples contribute to the growing number of existing mutations that affect short regions of the L1 protein that may have particular functional significance.

    Human mutation 1997;9;6;512-8

  • Five novel mutations in the L1CAM gene in families with X linked hydrocephalus.

    Gu SM, Orth U, Veske A, Enders H, Klunder K, Schlosser M, Engel W, Schwinger E and Gal A

    Institut fur Humangenetik, Medizinische Universitat zu Lubeck, Germany.

    Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence of L1CAM at the cell surface. The two missense mutations (Tyr194Cys and Pro240Leu) may considerably alter the structure of the L1CAM protein. These data provide convincing evidence that XHC is genetically extremely heterogeneous.

    Journal of medical genetics 1996;33;2;103-6

  • New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

    Jouet M, Moncla A, Paterson J, McKeown C, Fryer A, Carpenter N, Holmberg E, Wadelius C and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, United Kingdom.

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

    American journal of human genetics 1995;56;6;1304-14

  • X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene.

    Fransen E, Schrander-Stumpel C, Vits L, Coucke P, Van Camp G and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;12;2255-6

  • Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus.

    Rosenthal A, Jouet M and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    A locus for X-linked hydrocephalus (HSAS), which is characterized by mental retardation and enlarged brain ventricles, maps to the same subchromosomal region (Xq28) as the gene for neural cell adhesion molecule L1. We have found novel L1 mRNA species in cells from affected members of a HSAS family containing deletions and insertions produced by the utilization of alternative 3' splice sites. A point mutation at a potential branch point signal in an intron segregates with the disease and is likely to be responsible for the abnormal RNA processing. These results suggest that HSAS is a disorder of neuronal cell migration due to disruption of L1 protein function.

    Nature genetics 1992;2;2;107-12

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

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