Dataset Information

Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes.

ABSTRACT: Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.

SUBMITTER: Tucker EJ

PROVIDER: S-EPMC8821714 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes.

Tucker Elena J EJ Bell Katrina M KM Robevska Gorjana G van den Bergen Jocelyn J Ayers Katie L KL Listyasari Nurin N Faradz Sultana Mh SM Dulon Jérôme J Bakhshalizadeh Shabnam S Sreenivasan Rajini R Nouyou Benedicte B Carre Wilfrid W Akloul Linda L Duros Solène S Domin-Bernhard Mathilde M Belaud-Rotureau Marc-Antoine MA Touraine Philippe P Jaillard Sylvie S Sinclair Andrew H AH

European journal of human genetics : EJHG 20211028 2

Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. ...[more]

PMID: 34707299

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Project description:Background and aimpremature ovarian insufficiency (POI) is defined as the menopause before 40 years of age, and its prevalence is reported to be two-fold higher in Iranian women than the average for woman globally. POI is associated with several cardio/cerebrovascular complications as well as an increased overall mortality. Genetic factors, and serum levels of minerals and vitamin D, have been reported to be related to the prevalence of POI. We have investigated the association between some POI -related genotypes with the serum levels of some important micronutrients.MethodsOne hundred and seventeen women with POI and 183 controls without any renal, hepatic, and thyroid abnormalities were recruited as part of the MASHAD study. Demographic and anthropometric features were recorded and blood samples were collected and processed. DNA was extracted from the buffy coat of blood samples from all participants and 8 POI-related single nucleotide polymorphisms (SNPs) were determined using ASO-PCR or Tetra ARMS-PCR. Serum minerals and vitamin D concentrations were measured using routine methods.ResultsIn women with POI, serum copper, phosphate, and calcium were significantly different for those with rs244715, rs16991615, and rs4806660 genotypes, respectively. In our control population, significant differences were also found in serum copper concentrations between different genotypes of rs4806660, rs7246479, rs1046089, and rs2303369. After adjusting for all confounding factors, the women with POI carrying TC genotype (rs4806660) had a lower risk to have serum copper levels < 80 (µg/dL) than those carrying a TT genotype. Furthermore, women with POI carrying GG genotype (rs244715) had a 6-fold higher risk to have serum copper levels > 155 than those carrying AA genotype.ConclusionThe C and G alleles of the rs4806660 and rs244715 polymorphisms respectively are independently associated with serum copper in women with POI. Further studies are necessary to investigate the association of serum copper and other micronutrients in women and other POI -related polymorphisms.

Dataset Information

Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes.

Publications

Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes.

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