Mutations in MSH5 in primary ovarian insufficiency.
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.
Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, P.R. China.
Ting
T
Guo
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.
Shidou
S
Zhao
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.
Shigang
S
Zhao
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China.
Min
M
Chen
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.
Guangyu
G
Li
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.
Xue
X
Jiao
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.
Zhao
Z
Wang
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.
Yueran
Y
Zhao
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.
Yingying
Y
Qin
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China.
Fei
F
Gao
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.
Zi-Jiang
ZJ
Chen
D000328:Adult; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000473:pathology; D035781:Siblings
D018797:Cell Cycle Proteins; C118481:MSH5 protein, human