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

Abstract

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.

An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).

“…Previously reported mutations in or near putative branchpoint regions of human premRNA were shown to be associated with the use of alternative splice sites (9,30), enhanced efficiency of splicing (31) or exon skipping (32). We investigated, therefore, whether the observed intron retention also occurred in our index patient and identified two LCAT mRNA species in her leukocytes: a product of a size that would be expected after correct splicing of intron sequence, and a larger mutant product.…”

“…Although much is known about the highly conserved branchpoint region in yeast, the knowledge of the far less conserved mammalian sequence is limited with regard to the requirements which ensure its use as a branchpoint in lariat formation and consequently correct splicing. In 1993, Rosenthal et al (9) suggested an association between a mutation in a putative branchpoint region and the use of alternative splice sites in human pre-mRNA. We now provide unequivocal evidence that a mutation in such a sequence can cause intron retention and consequently results in a null allele.…”

Activation of the MAPK Signal Cascade by the Neural Cell Adhesion Molecule L1 Requires L1 Internalization

“…Mutations in the human L1 gene cause abnormal brain development, characterized by mental retardation and defects in central nervous system axon tracts such as the corpus callosum and corticospinal tract (Ref. 10 and for review see Ref. 11).…”

Deletion of a branch-point consensus sequence in the LMX1B gene causes exon skipping in a family with nail patella syndrome

“…9 Such mutations have been found associated with X-linked hydrocephalus, 10 hepatic lipase deficiency, 11 fish-eye disease, 12 congenital contractual arachnodactyly, 13 Sandhoff disease, 14 and Ehlers-Danlos syndrome. 15 These mutations resulted in cryptic splicing, 10,11,14 intron retention 12 and exon skipping. 13,15 That only a handful of such mutations have been identified may reflect the lack of stringency both within the branchpoint consensus, and the flexibility in distance from branchpoint to splice acceptor, that the splicing machinery can tolerate.…”