MCM8 and MCM9 Nucleotide Variants in Women with Primary Ovarian Insufficiency

Abstract

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.

Estrogen activates Alzheimer's disease genes

“…4). This finding provides robust independent support that menopause could underlie AD vulnerability in women because MCM8 has been strongly associated with primary ovarian insufficiency [60] and early menopause in women [61]. We also found excess mutations in female AD cases in the CCT7 and MCAT genes; which is interesting because our macaque data reveal CCT7 to have the highest estrogen‐induced fold change in neurons(Table 1, Supplementary Table 1) and MCAT is a mitochondrial enzyme.…”

“…We used genomic data spanning multiple data types to cross validate our findings on estrogen loss and AD risk. We found excess deleterious singleton mutations in the ovarian failure [60,68–71] and early menopause [61,72–76] gene MCM8 (Table 2, Supplementary Table 11), providing robust support for our hypothesis that estrogen loss at menopause confers increased vulnerability to AD in women. This finding fits with previous studies that have linked surgical menopause to doubled lifetime risk for dementia [23], increased risk for AD neuropathology [22] and cognitive decline [22].…”

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

“…Only one variant, c.911A>G (p.N304S; population minor allele frequency, MAF GnomAD = 0.35%), predicted benign, was identified in heterozygosity in an individual with 21–50 polyps and with relatives affected with colorectal polyposis, CRC, and breast and cervix tumors (Table S1). This variant had been previously reported in heterozygosity in two patients with POI, but its role in the disease causation was unknown (Desai et al, ). The relatively high frequency of this variant in population‐based databases (MAF GnomAD = 0.35%), the lack of predicted impact on protein functionality, and the lack of colonic findings in the two carriers with POI suggest no causal association of c.911A>G with polyposis.…”

“…One of the patients carried two heterozygous variants (one splice‐site and one predicted neutral) but their cis / trans phase was not determined. Another MCM9 heterozygous carrier (c.911A>G; p.N304S) also harbored a predicted neutral (REVEL) variant in MCM8 (c.1561G>A; p.D521N) (Desai et al, ). That same year, a homozygous nonsense mutation (c.1483G>T; p.E495*) was identified in two POI‐affected sisters from a consanguineous Middle Eastern family of Arab origin (Fauchereau et al, ).…”

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

“…Instead, the MCM8-9 complex has been implicated in HR in both mitotic and meiotic cells [11][12][13] . Consistently, MCM8-and MCM9-null female mice are sterile 13,14 and women carrying biallelic mutations in MCM8-9 exhibit Primary Ovarian Insufficiency (POI), a genetic syndrome characterized by reduced reproductive lifespan 15,16 . Furthermore, as a consequence of their role in HR, MCM8-and MCM9deficient cells are particularly sensitive to DNA interstrand crosslinking agents and PARP inhibition 11,12,17 .…”