Mutations in MSH5 in primary ovarian insufficiency

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 homozygousmissensemutation (ENST00000375755: c.1459G>T, p. D487Y) in theMSH5 gene in two sisters with POI. The homologous mutation inmice resulted in atrophic ovaries without oocytes, and in vitro functional study revealed thatmutantMSH5 impaired DNA homologous recombination repair. From sanger sequencing of MSH5 in 200 sporadic POI patients, we identified three heterozygousmutations (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 heterozygousmutations in POI needmore 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.