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 autosomaldominant trait characterized by tumors of the parathyroids, gastro-intestinal endocrine tissue, anterior pituitary and other tissues. Werecently cloned the MEN1 gene and confirmed its identity by findingmutations in FMEN1. We have now extended our mutation analysis to 34 moreunrelated FMEN1 probands and to two related states, sporadic MEN1 andfamilial hyperparathyroidism. There was a high prevalence of heterozygousgermline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation.Eight different mutations were observed more than once in FMEN1. Fortydifferent mutations (32 FMEN1 and eight sporadic MEN1) were distributedacross the MEN1 gene. Most predicted loss of function of the encoded meninprotein, supporting the prediction that MEN1 is a tumor suppressor gene. NoMEN1 germline mutation was found in five probands with familialhyperparathyroidism, suggesting that familial hyperparathyroidism often iscaused by mutation in another gene or gene(s).