Endocrine Abstracts

Multiple endocrine neoplasia type 1 (MEN1 – OMIM 131100) is considered as the major hereditary syndrome predisposing to multifocal endocrine tumors and a broad spectrum of non-endocrine lesions. Since the cloning of the MEN1 gene in 1997, a large number of studies have shown the large diversity of germline mutations found in patients with a poor genotype – phenotype correlation. Menin, the protein encoded by the MEN1 gene interacts with more than 30 nuclear/cellular factors (menin interacting proteins or MIP’s) involved in major processes of cell life. Among them, JunD, a negative regulator of the AP1 transcription factor, and mSin3A, a cofactor of chromatin remodeling complexes, are critical determinants of the functional pathway involving menin in the negative regulation of cell proliferation. A powerful network, called Groupe d’étude des Tumeurs Endocrines (GTE) has been initiated in France in 1995 and represents today a comprehensive database on MEN1 patients identified through clinical centers in the whole country. In a recent study on a cohort of 806 patients from a total of 262 families, we reported that the overall risk of death directly related to MEN1 tumors was significantly higher when mutations affected the JunD interacting domain. Such a correlation should thus be considered for surgical indications, genetic counseling and clinical follow-up. From these first epidemiological studies, we focus on the putative data provided by a large cohort studies, in relation to the functional areas of interaction with the MIP’s. Preliminary data are also presented on a number of missense variants which have been initially considered as polymorphisms, and shown to disrupt functional interactions of menin. These studies show that specific genotype phenotype correlations, unidentifiable with the ‘old’ series of mutations, may now be characterized by working on very large cohorts of patients for which complete clinical and genetic information have been collected.