POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women

Abstract

ContextPrimary ovarian insufficiency (POI) results from a premature loss of oocytes, causing infertility and early menopause. The etiology of POI remains unknown in a majority of cases.ObjectiveTo identify candidate genes in families affected by POI.DesignThis was a family-based genetic study.SettingThe study was performed at two academic institutions.Patients and Other ParticipantsA family with four generations of women affected by POI (n = 5). Four of these women, three with an associated autoimmune diagnosis, were studied. The controls (n = 387) were recruited for health in old age.InterventionWhole-genome sequencing was performed.Main Outcome MeasureCandidate genes were identified by comparing gene mutations in three family members and 387 control subjects analyzed simultaneously using the pedigree Variant Annotation, Analysis and Search Tool. Data were also compared with that in publicly available databases.ResultsWe identified a heterozygous nonsense mutation in a subunit of RNA polymerase II (POLR2C) that synthesizes messenger RNA. A rare sequence variant in POLR2C was also identified in one of 96 women with sporadic POI. POLR2C expression was decreased in the proband compared with women with POI from another cause. Knockdown in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation.ConclusionsThese data support a role for RNA polymerase II mutations as candidates in the etiology of POI. The current data also support results from genome-wide association studies that hypothesize a role for RNA polymerase II subunits in age at menopause in the population.

Characterization of a novel mutation V136L in bone morphogenetic protein 15 identified in a woman affected by POI

“…Several other genes have been reported to contribute to the genetic etiology of POI, including FMR1, FSHR, NOBOX, PGRMC1, GDF9, FOXO3, FIGLA, NR5A1, FOXL2, STAG3, SYCE1, HFM1, NUP107, MCM8, MCM9, MSH5, MSH4, KHDRBS1, EIF4ENIF1, PSMC3IP, CLPP and abnormal Y chromosome [ 3 ]. These genes are involved in various processes, including primordial germ cell development, DNA repair and meiosis, oocyte transcription and translational control during folliculogenesis, granulosa cell development and mitochondrial function [ 27 ]. The availability of the next-generation sequencing technology has resulted in a growing list of genes causing POI in the last years, revealing that it is a genetically complex disease [ 28 , 29 ].…”

Recent advances in understanding primary ovarian insufficiency

“…In that study, Polr3h D50G knockout mice exhibited delayed puberty and decreased litter size and decreased expression of the ovarian transcription factor forkhead box O3 (FOXO3) and fewer antral and primary follicles 17 . In a study of a family with four generations of women affected by POI, WGS identified a heterozygous nonsense mutation in an RNA polymerase II subunit, POLR2C 21 ; subsequent POLR2C knockdown in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation. These data support a role for RNA polymerase II and III mutations as candidates in the etiology of POI.…”

Pregnancy following diagnosis of premature ovarian insufficiency: a systematic review

“…Genetic causes are mostly caused by X chromosome abnormalities, including Turner syndrome (4-5%), triple X syndrome (1-4%), fragile X premutations (3-15%) and translocations involving the X chromosome. Recently, several genes have been implicated in the involvement of the pathogenesis of POI,including NOBOX,FOXO3,GDF9 and BPM15 variants (Joop, 2016;Moriwaki et al, 2017;Rossetti et al, 2017). Iatrogenic causes mainly stem from oncological treatments, such as chemotherapy, radiotherapy or extensive surgery; on occasion, they may follow surgical treatment of ovarian endometriosis or benign ovarian cystic disease (Iwase et al, 2014).…”