Internally shortened menin protein as a consequence of alternative RNA splicing due to a germline deletion in the multiple endocrine neoplasia type 1gene

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominantly inhe rited cancer syndrome (OMIM 131100), with tumours in several endocrine glan ds. In 1997 the responsible tumour suppressor gene was identified and recen tly it was shown that menin, its encoded protein, represses JunD-activated gene expression. Although many MEN 1 patients have been investigated both c linically and genetically, no genotype-phenotype correlation has been found yet. The vast majority of MEN 1 gene mutations involve point mutations. We describe a patient in whom a 26 base pair deletion in the MEN 1 gene, comp rising part of exon 3 and part of intron 3, causes activation of a cryptic donor splice site at the beginning of exon 3. This germline mutation result s in an in frame deletion of 105 nucleotides in MEN 1 gene mRNA, i.e. an in ternal deletion of 35 amino acids in the menin protein. Since the deleted r egion of menin has been implicated in binding to JunD, this may explain the tumourigenic effect of this mutation. The knowledge of this MEN 1 gene ger mline defect, may be used for presymptomatic identification of MEN 1 diseas e gene-carriers among family-members of this proband. This enables early de tection of tumour development, timely treatment and genetic counseling.