Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency
Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency
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DOI：
10.1172/jci61014
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发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Jouanguy, Emmanuelle
中科院分区：
文献类型：
--
作者：
Gineau, Laure;Cognet, Celine;Jouanguy, Emmanuelle
自然杀伤（NK）细胞是循环细胞毒性淋巴细胞，在小鼠中发挥有效和非冗余的抗病毒活性和抗肿瘤活性;然而，它们在人类宿主防御中的功能仍不清楚。在这里，我们调查了6例常染色体隐性遗传性生长迟缓、肾上腺功能不全和选择性NK细胞缺乏的相关患者，其特征是缺乏CD 56（dim）NK亚群。利用连锁分析和精细定位，我们确定了致病基因，MCM 4，它编码的DNA复制所需的MCM 2 -7解旋酶复合物的一个组成部分。患者的剪接位点突变产生了移码，但由于在提前终止密码子下游产生了两个新的翻译起始甲硫氨酸密码子，该突变是亚型的。患者的成纤维细胞表现出基因组不稳定性，这是由WT MCM 4的表达拯救的。这些数据表明，患者的生长迟缓和肾上腺功能不全可能反映了MCM 4突变在各种组织中的普遍但异质的影响。此外，患者中NK CD 56（dim）亚群的特异性丢失与NK CD 56（bright）细胞增殖率较低相关，并且NK CD 56（bright）细胞向NK CD 56（dim）表型的成熟密切依赖于MCM 4依赖性细胞分裂。因此，部分MCM 4缺乏导致生长迟缓伴肾上腺功能不全和选择性NK缺乏的遗传综合征。
Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56(dim) NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients' fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients' growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56(dim) subset in patients was associated with a lower rate of NK CD56(bright) cell proliferation, and the maturation of NK CD56(bright) cells toward an NK CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.