Introduction
Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF [MIM 311360]), is a hypergonadotropic disorder characterized by cessation of menses before 40 years of age and elevated level of follicle stimulating hormone (FSH) (1). Approximately, 1% of women in childbearing age are affected (2). POI is heterogeneous in etiology, including chromosomal abnormalities and single gene mutations, as well as autoimmune, metabolic, infectious and iatrogenic factors. While evidence from genetic factors, provided by population and candidate gene studies, is responsible for the pathogenesis of about 25% of cases, most cases remain unexplained (1). Recently, some novel causative genes have been identified by whole exome sequencing (WES) in POI pedigrees, such as HFM1 (MIM 615684), STAG3 (MIM 608489), MCM8 (MIM 608187), MCM9 (MIM 610098) and CSB-PGBD3 (MIM 609413) (3–7). Interestingly, all of these genes are involved in DNA repair or meiosis, which thus proposes a plausible brand-new concept for POI pathogenesis-inability to repair DNA damage.
MSH5 (MutS homologue 5) is a member of the MutS family, which is principally linked to mismatch repair (MMR). Among all the MSH homologs identified in eukaryotes, the MSH4-MSH5 heterodimers play an important role in homologous recombination (HR) repair for DNA double strand breaks (DSBs) (8). Meiotic crossing-over is processed by SPO11-dependent DSB and HR, hence, MSH5 is also involved in stabilizing and protecting the meiotic recombination intermediate (9). Here, we present an autosomal recessive causative mutation in MSH5 responsible for two sisters with POI in a Chinese non-syndromic kindred.