2. Academic Validation
  3. Mutations in MSH5 in primary ovarian insufficiency

Mutations in MSH5 in primary ovarian insufficiency

  • Hum Mol Genet. 2017 Apr 15;26(8):1452-1457. doi: 10.1093/hmg/ddx044.
Ting Guo 1,  Shidou Zhao 2,  Shigang Zhao 2,  Min Chen 3,  Guangyu Li 2,  Xue Jiao 2,  Zhao Wang 2,  Yueran Zhao 2,  Yingying Qin 2,  Fei Gao 3,  Zi-Jiang Chen 1 2
Affiliations

Affiliations

  • 1 Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, P.R. China.
  • 2 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.
  • 3 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China.
PMID: 28175301 DOI: 10.1093/hmg/ddx044
Abstract

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.

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