Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: Search for correlation between phenotype and the functional domains of the MEN1 protein

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by endocrine tumors of the parathyroids, the pancreatic islets, and the anterior pituitary. The MEN1 gene encodes menin, a nuclear protein interacting with JunD/AP1, Smad3, NFkappaB, and other proteins involved in transcription and cell growth regulation. Here, by exhaustive sequence analysis of 170 probands/families collected through a French clinical network, we identified 165 mutations located in coding parts of the MEN1 gene, which represent 114 distinct MEN1 germline alterations. These mutations have been included in a MEN1-locus specific database available on the world wide web together with approximate-to 240 germline and somatic MEN1 mutations listed from international published data. Our mutation series included 56 frameshifts, 23 nonsense, 27 missense, and eight deletion or insertion in-frame mutations. Mutations were spread over the entire coding sequence. Taken together, most missense and in-frame MEN1 genomic alterations affect one or all domains of menin interacting with JunD [codons 1-40; 139-242; 323-428], Smad3 [distal to codon 478], and NFkappaB [codons 276-479], three major effectors in transcription and cell growth regulation. No correlation has been observed between genotype and MEN1 phenotype. We suggest that the knowledge of structure and location of a specific mutation has not been useful in clinical practice for the follow-up of affected patients and asymptomatic gene carriers. Our results provide the largest series of MEN1 mutations published to date. They will be a useful tool for further studies focusing on the functional effects of missense mutations and understanding which mechanisms or pathways related to multiple menin interactions might be involved in tumorigenesis of endocrine cells.