A family of MEN1 with a novel germline missense mutation and benign polymorphisms

The gene responsible for multiple endocrine neoplasia type 1 (MEN1) has rec ently been cloned, and its germline mutations were identified in patients w ith this syndrome. The majority of the mutations, frameshift or nonsense mu tations, are expected to result in a loss of function of the gene product m enin. Since the consequence of less common missense or in-frame deletion mu tations is not clear, careful judgment is necessary regarding the role(s) o f such mutations in MEN1 disease. Here we describe a large multigenerationa l MEN1 family with a novel germline missense mutation and three benign poly morphisms. The proband was a man with hyperparathyroidism and thymic carcin oid. We performed biochemical studies and DNA analyses of the MEN1 gene sim ultaneously and independently as family screening studies. Seven patients i ncluding the proband were identified, and all of them carried a heterozygou s germline missense mutation E45G, but 5 members with normal biochemical re sults did not. This mutation was not observed in 50 normal volunteers. This novel missense mutation is therefore almost conclusively responsible for t he disease. Although all of the mutant gene carriers in the present study a lready had clinical diseases, an MEN1 gene analysis in younger individuals at risk would be very useful in identifying carriers before the onset of th e symptoms.