Guo Ting, Zhao Shidou, Zhao Shigang, Chen Min, Li Guangyu, Jiao Xue, Wang Zhao, Zhao Yueran, Qin Yingying, Gao Fei, Chen Zi-Jiang
Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, P.R. China.
Center for Reproductive Medicine, Shandong University, Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250021, P.R. China.
Hum Mol Genet. 2017 Apr 15;26(8):1452-1457. doi: 10.1093/hmg/ddx044.
Primary ovarian insufficiency (POI) is a genetically heterogeneous disorder that occurs in familial or sporadic fashion. Through whole exome sequencing in a Chinese pedigree with POI, we identified a novel homozygous missense mutation (ENST00000375755: c.1459G > T, p.D487Y) in the MSH5 gene in two sisters with POI. The homologous mutation in mice resulted in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. From sanger sequencing of MSH5 in 200 sporadic POI patients, we identified three heterozygous mutations (ENST00000375755: c.1057C > A, p.L353M; c.1459G > T, p.D487Y and c.2107 A > G, p.I703V). Considering the heterozygous p.D487Y carrier in the POI pedigree was fertile, the causality of the three heterozygous mutations in POI need more evidence. Our studies confirmed that perturbation of genes involved in DNA damage repair could lead to non-syndromic POI. The underlying mechanism-inability to repair DNA damage-will receive increasing attention with respect to POI.
原发性卵巢功能不全（POI）是一种以家族性或散发性方式出现的基因异质性疾病。通过对一个患有POI的中国家系进行全外显子组测序，我们在两名患有POI的姐妹中，于MSH5基因中鉴定出一个新的纯合错义突变（ENST00000375755: c.1459G > T, p.D487Y）。小鼠中的同源突变导致卵巢萎缩且无卵母细胞，体外功能研究表明突变型MSH5损害了DNA同源重组修复。通过对200例散发性POI患者的MSH5进行桑格测序，我们鉴定出三个杂合突变（ENST00000375755: c.1057C > A, p.L353M；c.1459G > T, p.D487Y和c.2107 A > G, p.I703V）。考虑到POI家系中的杂合p.D487Y携带者可育，这三个杂合突变在POI中的因果关系需要更多证据。我们的研究证实，参与DNA损伤修复的基因扰动可导致非综合征性POI。潜在机制——无法修复DNA损伤——在POI方面将受到越来越多的关注。
