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, Shaohua; Orth, Ulrike; Zankl, M.; Schröder, Jutta; Gal, Andreas

doi:10.1002/(sici)1096-8628(19970822)71:3<336::aid-ajmg15>3.0.co;2-l

Cited by 23 publications

(12 citation statements)

References 14 publications

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“…Forty‐six mutations are considered as disease causing (30.1% detection rate). Twelve of them were published previously by Gu et al [1996, 1997]. Three of the remaining 34 mutations have already been found in other, most likely unrelated families, 1108G→A [Ruiz et al, 1995], 1672C→T [] and 550C→T [Fransen et al, 1996].…”

Section: Resultsmentioning

confidence: 99%

“…In all cases where a sufficient number of family members was available, segregation analysis was performed using DXS52, DXS15, BGN, and F8C. PCR and SSCP analyses of the 28 coding exons (exons 1b‐28) were performed in all cases as described previously [Bunge et al, 1996; Gu et al, 1997]. In addition to the coding regions, the recently described 5′‐noncoding regions containing the human sites homologous to murine HPD (located upstream of the first coding exon, i.e., in intron 1a) and NRSE (located downstream of the first coding exon, i.e., in intron 1b) elements [Meech et al, 1999] were also screened.…”

Section: Methodsmentioning

confidence: 99%

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Spectrum and detection rate ofL1CAM mutations in isolated and familial cases with clinically suspected L1-disease

et al. 2000

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Spectrum and detection rate ofL1CAM mutations in isolated and familial cases with clinically suspected L1-disease

et al. 2000

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“…DNAs were PCR-amplified for each of the 28 coding exons of the L1CAM gene using intronic primers. SSCP analysis was performed as previously reported (Gu et al, 1996;Gu et al, 1997). The mutation identified in proband #1 and patient #2 resulted in the generation of a new restriction site for Hph I in amplicon 6, which was analyzed by agarose gel electrophoresis.…”

Section: L1cam Mutation Analysismentioning

confidence: 99%

“…The gene contains 29 exons, of which 28 include coding regions (Kallunki et al, 1997). In human, L1CAM mutations have been shown to be associated with a group of related neurological disorders, L1 disease, (Gu et al, 1996;Gu et al, 1997;Jouet et al, 1994;Rosenthal et al, 1992;Van Camp et al, 1993;Vits et al, 1994), occurring in about 1:25.000 to 1:60.000 males. The most consistent clinical findings are mental retardation and a hypoplastic or absent corticospinal tract.…”

Section: Introductionmentioning

confidence: 99%

Intronic mutations in theL1CAMgene may cause X-linked hydrocephalus by aberrant splicing

et al. 2004

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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 w ithin 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.

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“…Therefore, these syndromes have been reclassified as L1 syndrome. 2,4,[7][8][9][10][11]17 The L1CAM gene is located on the X chromosome in humans and is composed of 28 exons. The open reading frame has 3825 bp that encode a protein of 1257 amino acids.…”

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confidence: 99%

Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus)

Yamasaki

Nonaka

Suzumori

et al. 2011

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Object The aim of this study was to evaluate the feasibility of prenatal L1CAM gene testing for X-linked hydrocephalus (XLH). Methods In a nationwide study conducted in Japan between 1999 and 2009, the authors identified 51 different L1CAM gene mutations in 56 families with XLH. Of these 56 families, 9 obligate carriers requested prenatal gene mutation analysis for the fetal L1CAM gene in 14 pregnancies. Results In 2004, new clinical guidelines for genetic testing were established by 10 Japanese genetic medicine–related societies. These guidelines stated that the genetic testing of carriers should be done only with their consent and with genetic counseling. Therefore, because females are carriers, since 2004, L1CAM gene analysis has not been performed for female fetuses. The authors report on 7 fetal genetic analyses that were performed at the request of families carrying L1CAM mutations, involving 3 female (prior to 2004) and 4 male fetuses. Of the 7 fetuses, 3 (1 male and 2 female) carried L1CAM mutations. Of these 3, 1 pregnancy (the male fetus) was terminated; in the other cases, the pregnancies continued, and 3 female and 3 male babies without the XLH phenotype were born. Conclusions Prenatal L1CAM gene testing combined with genetic counseling was beneficial for families carrying L1CAM mutations.

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

Cited by 23 publications

References 14 publications

Spectrum and detection rate ofL1CAM mutations in isolated and familial cases with clinically suspected L1-disease

Spectrum and detection rate ofL1CAM mutations in isolated and familial cases with clinically suspected L1-disease

Intronic mutations in theL1CAMgene may cause X-linked hydrocephalus by aberrant splicing

Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus)

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