p.A1a541Thr variant of MEN1 gene: A non deleterious polymorphism or a pathogenic mutation?

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.A1a541Thr 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.A1a541Thr variant on clinical and functional outcomes. Patients and methods. We analysed a series of 55 index patients carrying the p.A1a541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.A1a541Thr 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.A1a541Thr carriers and MEN1 patients, but no p.A1a541Thr 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.A1a541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.A1a541Thr 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.A1a541Thr 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. (C) 2014 Elsevier Masson SAS. All rights reserved.