A SILENT MUTATION, C924T (G308G), IN THE L1CAM GENE RESULTS IN X-LINKED HYDROCEPHALUS (HSAS)

The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in t he development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation condi tions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardatio n, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X Linked agenesis of the corpus callosum (ACC). In an an alysis 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 affect ed male fetus and subsequent sequence analysis confirmed the use of th e new splice site, This is the first report of a silent nucleotide sub stitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more imp ortant role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.