title: Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University Hospital Eppendorf, Hamburg, Germany. c.huebner@uke.uni-hamburg.de
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Barbara
authors.initials: B
authors.lastname: Utermann
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.forename: Gabriele
authors.initials: G
authors.lastname: Krüger
authors.forename: Bernadette
authors.initials: B
authors.lastname: Ressler
authors.forename: Cordula
authors.initials: C
authors.lastname: Steglich
authors.forename: Albert
authors.initials: A
authors.lastname: Schinzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D006849:Hydrocephalus / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics*; D010375:Pedigree; D012326:RNA Splicing
chemical_list: D039842:Neural Cell Adhesion Molecule L1