Dataset Information

MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.

ABSTRACT: Objective:To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). Design:MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. Setting:Academic research institution. Participants:All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels. Interventions:None. Main Outcome Measures:We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. Results:MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway. Conclusions:We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.

SUBMITTER: Desai S

PROVIDER: S-EPMC5413161 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.

Desai Swapna S Wood-Trageser Michelle M Matic Jelena J Chipkin Jaqueline J Jiang Huaiyang H Bachelot Anne A Dulon Jerome J Sala Cinzia C Barbieri Caterina C Cocca Massimiliano M Toniolo Daniela D Touraine Philippe P Witchel Selma S Rajkovic Aleksandar A

The Journal of clinical endocrinology and metabolism 20170201 2

<h4>Objective</h4>To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI).<h4>Design</h4>MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants.<h4>Setting</h4>Academic research institution.<h4>Pa ...[more]

PMID: 27802094

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Project description:STUDY QUESTION:What is the prevalence of somatic chromosomal instability among women with idiopathic primary ovarian insufficiency (POI)? SUMMARY ANSWER:A subset of women with idiopathic POI may have functional impairment in DNA repair leading to chromosomal instability in their soma. WHAT IS KNOWN ALREADY:The formation and repair of DNA double-strand breaks during meiotic recombination are fundamental processes of gametogenesis. Oocytes with compromised DNA integrity are susceptible to apoptosis which could trigger premature ovarian aging and accelerated wastage of the human follicle reserve. Genomewide association studies, as well as whole exome sequencing, have implicated multiple genes involved in DNA damage repair. However, the prevalence of defective DNA damage repair in the soma of women with POI is unknown. STUDY DESIGN, SIZE, DURATION:In total, 46 women with POI and 15 family members were evaluated for excessive mitomycin-C (MMC)-induced chromosome breakage. Healthy fertile females (n = 20) and two lymphoblastoid cell lines served as negative and as positive controls, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS:We performed a pilot functional study utilizing MMC to assess chromosomal instability in the peripheral blood of participants. A high-resolution array comparative genomic hybridization (aCGH) was performed on 16 POI patients to identify copy number variations (CNVs) for a set of 341 targeted genes implicated in DNA repair. MAIN RESULTS AND THE ROLE OF CHANCE:Array CGH revealed three POI patients (3/16, 18.8%) with pathogenic CNVs. Excessive chromosomal breakage suggestive of a constitutional deficiency in DNA repair was detected in one POI patient with the 16p12.3 duplication. In two patients with negative chromosome breakage analysis, aCGH detected a Xq28 deletion comprising the Centrin EF-hand Protein 2 (CETN2) and HAUS Augmin Like Complex Subunit 7 (HAUS7) genes essential for meiotic DNA repair, and a duplication in the 3p22.2 region comprising a part of the ATPase domain of the MutL Homolog 1 (MLH1) gene. LIMITATIONS REASONS FOR CAUTION:Peripheral lymphocytes, used as a surrogate tissue to quantify induced chromosome damage, may not be representative of all the affected tissues. Another limitation pertains to the MMC assay which detects homologous repair pathway defects and does not test deficiencies in other DNA repair pathways. WIDER IMPLICATIONS OF THE FINDINGS:Our results provide evidence for functional impairment of DNA repair in idiopathic POI, which may predispose the patients to other DNA repair-related conditions such as accelerated aging and/or cancer susceptibility. STUDY FUNDING/COMPETING INTEREST(S):Funding was provided by the National Institute of Child Health and Human Development. There were no competing interests to declare.

Dataset Information

MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.

Publications

MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.

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