Mutation and Functional Analysis of the MEN1 Gene

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Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by the multiple occurrences of endocrine tumors in the pituitary, parathyroid, and enteropancreatic endocrine tissues. Germline mutations of the causative gene MEN1 are known to cause not only typical MEN1 but also a milder form, familial isolated hyperparathyroidism (FIHP), in which endocrine tumors other than parathyroid adenomas do not appear in the pedigree. The patients initially diagnosed as having FIHP and carrying a germline MEN1 mutation often turn out to exhibit typical MEN1 manifestations later. On the other hand, some missense mutations are likely to be specifically associated with FIHP. It is difficult to know whether or not a germline missense mutation newly found in parathyroid adenoma patients would eventually cause typical MEN1. In our previous studies, menin, the MEN1 gene product, was shown to be fairly stable in the cells while missense mutants causing typical MEN1 were demonstrated to degrade rapidly. A diagnostic test for predicting the prognosis of missense MEN1 mutant carriers has been developed by exploiting this stability difference. The stability of various missense menin mutants associated with MEN1, FIHP or apparently sporadic parathyroid tumors (ASPTs) was compared with that of wild-type menin in culture cells by transfection-expression experiments. All tested mutants causing typical MEN1 were unstable and degraded rapidly. In contrast, some missense mutants associated with FIHP and ASPTs exhibited stability comparable with those of wild-type menin and normal polymorphic menin variants. These findings suggest that long-term follow-up for MEN1 is necessary for ASPT patients who carry a missense MEN1 mutation resulting in an unstable protein product.