Germline mutation profile ofMEN1in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein

Abstract

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 approximately 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.

The clinical, pathological, and genetic features of familial isolated pituitary adenomas

“…These data are supported by murine models of men1 gene knockout, in which w37% of heterozygotic animals had pituitary tumors in adulthood (8). While no genotype-phenotype relation has been shown among the hundreds of MEN1 mutations now described, in familial MEN1, pituitary disease is significantly more frequent than in sporadic MEN1 cases (9). Prolactinomas predominate in MEN1, are larger than their sporadic counterparts and have a poorer response to dopamine agonist therapy (7).…”

Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database

“…Mutation analysis of the MEN1 gene allows the early identification of asymptomatic carriers, years before any MEN1-associated biochemical and/or instrumental abnormalities are detected [6,8]. Unfortunately, as reported by the great majority of worldwide epidemiology studies, a genotype-phenotype correlation, like in MEN2 syndromes, has not clearly been identified in MEN1 syndrome, strongly reducing the possibility to foresee exact future clinical manifestations of the disease by the specific gene mutation [6,[9][10][11][12]. Recently, two studies by the "Groupe d'étude des tumors endocrines (GTE)" reported a trend for intrafamilial correlation in disease expression and severity and in heritability of MEN1 tumors [13,14].…”

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

“…However, no clinically relevant genotype-phenotype correlation has been established to date. (7,13) A diagnostic DNA test for MEN1 germline mutations is beneficial to the patients with endocrine tumors suggestive of MEN1 and offspring of MEN1 patients.(2) However, it is often difficult to distinguish a disease-causing mutation from a rare benign polymorphism especially when it is a novel missense mutation found in a patient with incomplete forms of MEN1. We previously demonstrated that menin missense mutants associated with typical MEN1, defined as the occurrence of tumors in at least two of the three main MEN1-related endocrine tissues, are degraded rapidly by the ubiquitin-proteasome pathway when expressed in culture cells.…”

“…However, no clinically relevant genotype-phenotype correlation has been established to date. (7,13) A diagnostic DNA test for MEN1 germline mutations is beneficial to the patients with endocrine tumors suggestive of MEN1 and offspring of MEN1 patients.…”

“…However, no clinically relevant genotype-phenotype correlation has been established to date. (7,13) A diagnostic DNA test for MEN1 germline mutations is beneficial to the patients with endocrine tumors suggestive of MEN1 and offspring of MEN1 patients. (2) However, it is often difficult to distinguish a disease-causing mutation from a rare benign polymorphism especially when it is a novel missense mutation found in a patient with incomplete forms of MEN1.…”