p.Ala541Thr variant of MEN1 gene: A non deleterious polymorphism or a pathogenic mutation?

• Published in: Annales d'endocrinologie Vol. 75; no. 3; pp. 133 - 140
• Main Authors: Nozières, Cecile, Zhang, Chang-Xian, Buffet, Alexandre, Dupasquier, Stéphanie, Vargas-Poussou, Rosa, Guillaud-Bataille, Marine, Cordier-Bussat, Martine, Ruszniewski, Philippe, Christin-Maitre, Sophie, Murat, Arnaud, Groussin, Lionel, Vezzosi, Delphine, Cardot-Bauters, Catherine, Hervieu, Valérie, Joly, Marie-Odile, Giraud, Sophie, Odou, Marie-Françoise, Gimenez-Roqueplo, Anne-Paule, Goudet, Pierre, Borson-Chazot, Françoise, Calender, Alain
• Format: Journal Article
• Language: English
• Published: Paris Elsevier Masson SAS 01.07.2014; Masson; Société française d'endocrinologie [1939-....]
• Subjects: Adenoma - genetics; Adult; Animals; Biological and medical sciences; Cell Line, Tumor; Endocrinology & Metabolism; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; General aspects. Associated endocrine diseases. Endocrine paraneoplasic syndromes; Heterozygote; Humans; Hyperparathyroidism - genetics; Internal Medicine; Leydig Cell Tumor - genetics; Life Sciences; Male; Medical sciences; Mice; Mice, Knockout; Middle Aged; Multiple endocrine neoplasia type 1; Multiple Endocrine Neoplasia Type 1 - genetics; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Néoplasie endocrinienne multiple de type 1; Penetrance; Phenotype; Pituitary Neoplasms - genetics; Polymorphism; Polymorphism, Genetic - genetics; Polymorphisme; Predisposition; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Prédisposition; Pénétrance; Transfection; Tumors; Vertebrates: endocrinology; Néoplasie endocrinienne multiple de type 1; Predisposition; Multiple endocrine neoplasia type 1; Penetrance; Mutation; Prédisposition; Polymorphisme; Pénétrance; Polymorphism; Endocrinopathy; Variant; Gene; Multiple endocrine neoplasia; Malignant tumor; Cancer; Genetic disease; Multiple Endocrine Neoplasia Type 1; penetrance; predisposition; néoplasie endocrinienne multiple de type 1; polymorphisme
• ISSN: 0003-4266; 2213-3941
• DOI: 10.1016/j.ando.2014.05.003

Abstract Context Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers. Objective The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes. Patients and methods We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1 + /Men1 − heterozygous knock-out mice, and compared with wild type (WT). Results The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein. Conclusion Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.