Clinical genetic study of MEN1: recent pathophysiological data and clinical applications

Multiple Endocrine Neoplasia type I (MEN1, OMIM 131100, Wermer syndrome) is characterized by inherited predisposition to primary hyperparathyroidism, endocrine pancreatic-duodenal, pituitary, adrenal glands tumors and benign and/or malignant proliferations of diffuse neuroendocrine tumors in thymus and bronchi, formerly defined as carcinoid tumors. Minor lesions have been observed in MEN1 patients such as cutaneous tumors (angiofibroma, lipoma, l entiginosis), thyroid epithelioma and tumors of the central nervous system, mainly spinal ependymoma. The MEN1 gene, a locus encompassing a 9kb of gen omic sequence contains 10 exons, the first exon being untranslated. The pro tein encoded by this gene was called menin and has been shown to contain tw o nuclear localization signals (NLS), suggesting a major function in the nu cleus. Germline MEN1 mutations have been described in more than 150 familie s and are spread throughout the entire coding sequence. More than 70% of th e mutations alter one or both NLS and no genotype-phenotype correlations we re found to date. The MEN1 gene seems to be involved in a 20-30% of sporadi c parathyroid and pancreatic/bronchic neuroendocrine tumors, but less than 1% of pituitary sporadic tumors. Further knowledge on the intracellular fun ction of menin will be needed to understand the pathogenic effect of trunca ting and missense mutations of this gene in the initiation of endocrine cel ls tumorigenesis.