TY - JOUR T1 - MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency. JF - J Clin Endocrinol Metab Y1 - 2017 A1 - Desai, Swapna A1 - Wood-Trageser, Michelle A1 - Matic, Jelena A1 - Chipkin, Jaqueline A1 - Jiang, Huaiyang A1 - Bachelot, Anne A1 - Dulon, Jerome A1 - Sala, Cinzia A1 - Barbieri, Caterina A1 - Cocca, Massimiliano A1 - Toniolo, Daniela A1 - Touraine, Philippe A1 - Witchel, Selma A1 - Rajkovic, Aleksandar KW - Adult KW - Aging KW - DNA Damage KW - DNA Repair KW - Female KW - Humans KW - Minichromosome Maintenance Proteins KW - Primary Ovarian Insufficiency KW - Sequence Analysis, DNA AB -

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.

VL - 102 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27802094?dopt=Abstract ER -