Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)

Objective: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endo crine tumors involving the parathyroids, anterior pituitary and enteropancr eatic neuroendocrine tissues, and is inherited in an autosomal dominant man ner. Recently, the gene responsible for this syndrome, MEN1, was positional ly cloned in 11q13. We aimed to assess the significance of MEN1 gene diagno stics in families with MEN1. Design: Sixteen probands of familial MEN1 and their 40 family members were subjected to the study. Methods: Full-length sequencing of the open reading frame and exon-intron b oundaries in the MEN1 gene was performed with probands of familial MEN1. Fa mily members were examined for the identified mutation in the proband. Results: We identified heterozygous germline mutations of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the highest detectabil ity of MEN1 mutations in familial MEN1 among studies that examined more tha n 10 families. Eleven kinds of the identified MEN1 germline mutations were novel. More than half were nonsense or frameshift mutations resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no apparent genotype-phenotype relationships were observed, in support of the results o f other studies. We identified 40 mutant MEN1 gene carriers and 16 non-carr iers in the course of the present study in those families. Conclusions: Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands and family members o f MEN1, should be considered as a standard procedure and categorized as bel onging to Group 1 cancer predisposition testing by the American Society of Clinical Oncology.