Germline mutations in the MEN1 gene: Creation of a new splice acceptor site and insertion of 7 intron nucleotides into the mRNA

The MEN1 tumor predisposition syndrome is caused by mutations in the MEN1 g ene on human chromosome 11q13. We screened MEN1 gene exons 1-10 and flankin g intron sequences from four different MEN1 families for mutations. In thre e families, heterozygous germline mutations within the exons were found, tw o of these representing novel mutations. In another family, all clinically affected members were heterozygous for a point mutation G-->A within intron 4. Sequence analysis of cDNA from lymphocytes of the affected patients rev ealed that the intron mutation created a new acceptor splice site, leading to the inclusion of 7 bp of intronic sequence into the mRNA. The resulting frameshift generates a premature stop in codon 271. Intron borders should t hus be screened for mutations in MEN1 diagnostics and cDNA sequence analysi s is helpful in identifying pathophysiological consequences of intron mutat ions.