Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family.
Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family.
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全外显子组测序鉴定 MCM2 为中国家族常染色体显性非综合征性耳聋的新致病基因
DOI：
10.1371/journal.pone.0133522
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Gao J;Wang Q;Dong C;Chen S;Qi Y;Liu Y
我们报告了一家系中常染色体显性遗传性、非综合征进行性感音神经性耳聋的遗传分析。通过外显子全序列测定，我们在MCM2基因中发现了一个错义变异体(c.130C>；T，p.R44C)，它具有促细胞凋亡的作用，参与了真核生物基因组复制的启动。这种错义变异很可能是导致疾病的变异。在该家系中与听力损失分离，在中国人群、76例散发性耳聋患者和145例正常人中未发现该基因的存在。我们用免疫印迹和免疫荧光检测了MCM2蛋白在大鼠和豚鼠耳蜗组织中的表达，结果表明MCM2在耳蜗组织中广泛表达，在终末分化的毛细胞中也有令人惊讶的表达。然后我们在HEK293细胞中瞬时表达了MCM2变异基因，发现这些细胞表现出轻微的凋亡增加，而对细胞增殖和细胞周期没有任何改变，支持了该变异是致病的观点。综上所述，我们发现MCM2是一个新的常染色体显性遗传性非综合征性耳聋的致病基因。
We report the genetic analysis of autosomal dominant, nonsyndromic, progressive sensorineural hearing loss in a Chinese family. Using whole exome sequencing, we identified a missense variant (c.130C>T, p.R44C) in the MCM2 gene, which has a pro-apoptosis effect and is involved in the initiation of eukaryotic genome replication. This missense variant is very likely to be the disease causing variant. It segregated with hearing loss in this pedigree, and was not found in the dbSNP database or databases of genomes and SNP in the Chinese population, in 76 patients with sporadic hearing loss, or in 145 normal individuals. We performed western blot and immunofluorescence to test the MCM2 protein expression in the cochlea of rats and guinea pigs, demonstrating that MCM2 was widely expressed in the cochlea and was also surprisingly expressed in the cytoplasm of terminally differentiated hair cells. We then transiently expressed the variant MCM2 cDNA in HEK293 cells, and found that these cells displayed a slight increase in apoptosis without any changes in proliferation or cell cycle, supporting the view that this variant is pathogenic. In summary, we have identified MCM2 as a novel gene responsible for nonsyndromic hearing loss of autosomal dominant inheritance in a Chinese family.