MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans
MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans
复制标题
DOI：
10.1172/jci60224
复制
发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Metherell, Louise A.
中科院分区：
文献类型：
--
作者：
Hughes, Claire R.;Guasti, Leonardo;Metherell, Louise A.
家族性糖皮质激素缺乏症（FGD）是一种常染色体隐性遗传的肾上腺皮质功能衰竭，存在于一个遗传隔离的爱尔兰人群中。除了低皮质醇血症，受影响的儿童表现出生长障碍，染色体断裂增加和NK细胞缺乏的迹象。8例患者的靶向外显子组测序确定了微小染色体维持缺陷4（MCM 4）的一个变体（c.71- 1 insG），该变体预计会导致严重截短的蛋白质（p.Pro24ArgfsX4）。患者样本的蛋白质印迹法显示，主要的96 kDa的异构体存在于未受影响的人类对照是不存在的，而存在的次要的85 kDa的异构体被保留。有趣的是，Mcm 4缺失小鼠的组织学研究显示肾上腺形态严重异常，其特征在于类固醇生成皮质内的非类固醇生成GATA 4和Gli 1阳性细胞，这减少了肾上腺皮质束状体中类固醇生成细胞的数量。由于MCM 4是MCM 2 -7复合物的一部分，最近被证实为所有真核生物中正常DNA复制和基因组稳定性所必需的复制解旋酶，因此我们的患者可能会增加肿瘤变化的风险。总之，我们已经确定了我们认为是第一个人类MCM 4突变，并表明它与肾上腺功能不全，身材矮小和NK细胞缺乏症有关。
An interesting variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure, exists in a genetically isolated Irish population. In addition to hypocortisolemia, affected children show signs of growth failure, increased chromosomal breakage, and NK cell deficiency. Targeted exome sequencing in 8 patients identified a variant (c.71-1insG) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting of patient samples revealed that the major 96-kDa isoform present in unaffected human controls was absent, while the presence of the minor 85-kDa isoform was preserved. Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morphology that was characterized by non-steroidogenic GATA4- and Gli1-positive cells within the steroidogenic cortex, which reduced the number of steroidogenic cells in the zona fasciculata of the adrenal cortex. Since MCM4 is one part of a MCM2-7 complex recently confirmed as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes, it is possible that our patients may have an increased risk of neoplastic change. In summary, we have identified what we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal insufficiency, short stature, and NK cell deficiency.