Premium
Intronic mutations in the L1CAM gene may cause X‐linked hydrocephalus by aberrant splicing
Author(s) -
Hübner Christian A.,
Utermann Barbara,
Tinschert Sigrid,
Krüger Gabriele,
Ressler Bernadette,
Steglich Cordula,
Schinzel Albert,
Gal Andreas
Publication year - 2004
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9242
Subject(s) - biology , genetics , rna splicing , gene , mutation , intron , exon , rna
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. © 2004 Wiley‐Liss, Inc.