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
Fédération d'endocrinologie du Pôle Lyon-Est, université Lyon 1, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France; UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France.
UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France.
Ann Endocrinol (Paris). 2014 Jul;75(3):133-40. doi: 10.1016/j.ando.2014.05.003. Epub 2014 Jul 2.
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.
The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes.
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).
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.
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.
多发性内分泌腺瘤1型（MEN1）是一种常染色体显性遗传综合征，与MEN1基因突变有关。有争议的数据表明，通常被认为是一种非致病性多态性的非同义p.Ala541Thr变体，可能与携带者中MEN1相关病变风险增加有关。
本研究旨在评估p.Ala541Thr变体对临床和功能结果的致病影响。
我们分析了一系列携带p.Ala541Thr变体的55名索引患者。将他们的临床特征与117名MEN1患者的临床特征进行比较。此外，在从Men1+/Men1-杂合敲除小鼠产生的缺乏menin的睾丸间质细胞瘤（LCT）10细胞上研究p.Ala541Thr变体对细胞生长的生物学影响，并与野生型（WT）进行比较。
p.Ala541Thr携带者和MEN1患者首次出现内分泌病变的平均年龄相似，但在初始诊断时，没有p.Ala541Thr患者有超过一种主要的MEN1病变。在初步诊断后的一年内，13%的MEN1患者和7%的p.Ala541Thr携带者被诊断出第二种MEN1病变。对LCT10细胞的功能研究表明，p.Ala541Thr变体的过表达并未抑制细胞生长，这与对WT menin蛋白的研究结果形成直接对比。
综上所述，这些数据提出了menin的p.Ala541Thr错义变体在普通人群中普遍存在的潜在致病性问题。需要进一步研究以调查它是否可能与低外显率的MEN1表型有关。
