Human Molecular Genetics, Vol 7, 393-398, Copyright © 1998 by Oxford University Press
A De Klein, PH Riegman, EK Bijlsma, A Heldoorn, M Muijtjens, MA den Bakker, CJ Avezaat and EC Zwarthoff
We describe a G-->A transition within intron 5 of the NF2 gene. This
mutation creates a consensus splice branch point sequence. To our knowledge
this is the first report of a mutation that creates a functional branch
point sequence in a human hereditary disorder. The new branch point
sequence is located 18 bp upstream of a consensus splice acceptor site. A
consensus splice donor site is found 106 bp 3' of the acceptor site. Asa
consequence the G-->A transition results in an alternatively spliced
mRNA containing an additional exon 5a of 106 bp derived from intron
sequences. We cloned the mutant cDNA and show that due to an in-frame stop
codon the cDNA codes for a truncated NF2 protein. The mutation was observed
in three affected members of an NF2 family. In a tumour of one of the
family members both alternatively spliced and wild-type mRNA were found,
although the wild-type allele of the gene is absent due to an interstitial
deletion on chromosome 22. We also show that immunoprecipitations reveal
the presence of full-length wild-type NF2 protein in the tumour lysate.
These data support the hypothesis that some degree of normal splicing of
the mutant precursor RNA is taking place. It is therefore likely that this
residual activity of the mutant allele explains the relatively mild
phenotype in the family. These data also indicate that complete
inactivation of the gene is not required for tumour formation.
ARTICLES
A G-->A transition creates a branch point sequence and activation of a cryptic exon, resulting in the hereditary disorder neurofibromatosis 2
Department of Cell Biology, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
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