Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant trait characterized by tumors of the parathyroids, gastro-intestinal endocrine tissue, anterior pituitary and other tissues. We recently cloned the MEN1 gene and confirmed its identity by finding mutations in FMEN1. We have now extended our mutation analysis to 34 more unrelated FMEN1 probands and to two related states, sporadic MEN1 and familial hyperparathyroidism. There was a high prevalence of heterozygous germline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50 probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation. Eight different mutations were observed more than once in FMEN1. Forty different mutations (32 FMEN1 and eight sporadic MEN1) were distributed across the MEN1 gene. Most predicted loss of function of the encoded menin protein, supporting the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutation was found in five probands with familial hyperparathyroidism, suggesting that familial hyperparathyroidism often is caused by mutation in another gene or gene(s).