|
Comment |
Minichromosome maintenance complex component 8 and 9 gene expression in the menstrual cycle and unexplained primary ovarian insufficiency. Dondik Y et al. (2018) DNA repair genes Minichromosome maintenance complex component (MCM) 8 and 9 have been linked with gonadal development, primary ovarian insufficiency (POI), and age at menopause. Our objective was to characterize MCM 8 and 9 gene expression in the menstrual cycle, and to compare MCM 8/9 expression in POI vs normo-ovulatory women. Normo-ovulatory controls (n = 11) and unexplained POI subjects (n = 6) were recruited. Controls provided three blood samples within one menstrual cycle: (1) early follicular phase, (2) ovulation, and (3) mid-luteal phase. Six of 11 controls only provided a follicular phase sample. Amenorrheic POI subjects provided a single, random blood sample. MCM8/9 expression in peripheral blood was assessed with qRTPCR. Analyses were performed using delta-Ct measurements; group differences were transformed to a fold change (FC) and confidence interval (CI). Differences across menstrual cycle phases were compared using random effects ANOVA. Two-sample t tests were used to compare two groups. MCM8 expression was significantly lower at ovulation and during the luteal phase, when compared to the follicular phase [FC = 0.69 in the luteal vs follicular phase (p = 0.012, CI = 0.53, 0.90); and 0.65 in the ovulatory vs follicular phase (p = 0.0057, CI = 0.50, 0.85)]. No change in MCM9 expression was noted throughout the menstrual cycle. No significant difference was seen in MCM8/9 expression when comparing POI to control subjects. Our study showed greater MCM8 expression in the follicular phase of the menstrual cycle, compared to the ovulatory and luteal phases. No cyclic changes were seen with MCM9. Significant differences in MCM8/9 expression were not detected between POI and controls; however, we recommend further investigation with a larger sample population.//////////////////
|
|
Mutations |
5 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Genetic markers of ovarian follicle number and menopause in women of multiple ethnicities. Schuh-Huerta SM et al. Oocyte loss has a significant impact on fertility and somatic health. Yet, we know little about factors that impact this process. We sought to identify genetic variants associated with ovarian reserve (oocyte number as measured by antral follicle count, AFC). Based on recently published genome-wide scans that identified loci associated with age of menopause, we also sought to test our hypothesis that follicle number and menopausal age share underlying genetic associations. We analyzed menopause-related variants for association with follicle number in an independent population of approximately 450 reproductive-aged women of European and African ancestry; these women were assessed for AFC, anthropometric, clinical, and lifestyle factors. One SNP strongly associated with later menopausal age in Caucasian women (+1.07???0.11?years) in previous work was also associated with higher follicle counts in Caucasians (+2.79???1.67 follicles) in our study. This variant is within the Minichromosome Maintenance Complex Component 8 (MCM8) gene, which we found was expressed within oocytes in follicles of the human ovary. In genome-wide scans of AFC, we also identified one marginally genome-wide and several nominally significant SNPs within several other genes associated with follicle number in both ethnic groups. Further, there were overlapping variants associated with multiple ovarian reserve markers (AFC, serum hormone levels, menopausal age). This study provides the first evidence for direct genetic associations underlying both follicle number and menopause and identifies novel candidate genes. Genetic variants associated with ovarian reserve may facilitate discovery of genetic markers to predict reproductive health and lifespan in women.
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: MCM8- and MCM9-Deficient Mice Reveal Gametogenesis Defects and Genome Instability Due to Impaired Homologous Recombination. Lutzmann M et al. We generated knockout mice for MCM8 and MCM9 and show that deficiency for these genes impairs homologous recombination (HR)-mediated DNA repair during gametogenesis and somatic cells cycles. MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I, and females have only arrested primary follicles and frequently develop ovarian tumors. MCM9(-/-) females also are sterile as ovaries are completely devoid of oocytes. In contrast, MCM9(-/-) testes produce spermatozoa, albeit in much reduced quantity. Mcm8(-/-) and Mcm9(-/-) embryonic fibroblasts show growth defects and chromosomal damage and cannot overcome a transient inhibition of replication fork progression. In these cells, chromatin recruitment of HR factors like Rad51 and RPA is impaired and HR strongly reduced. We further demonstrate that MCM8 and MCM9 form a complex and that they coregulate their stability. Our work uncovers essential functions of MCM8 and MCM9 in HR-mediated DSB repair during gametogenesis, replication fork maintenance, and DNA repair.
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. AlAsiri S et al. (2014) Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability.//////////////////
Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Stolk L et al. (2010) We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 × 10(-11)), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10(-11)) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10(-8)). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.//////////////////The more significantly associated SNP from the imputed data is a nonsynonymous SNP in exon 9 of this gene (E341K), and could influence the protein structure or function of MCM8.
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature. Wang F et al. (2020) Minichromosome maintenance complex component 8 (MCM8) is responsible for homologous recombination and DNA double-strand breaks (DSBs) repair and is the cause of primary ovarian insufficiency (POI), which is seldom diagnosed in adolescents and children. Whole-exome sequencing was performed in a 13-year-old girl, and Sanger sequencing was used to identify potentially pathogenic variants in her sister (aged 6 years and 7 months) and parents. To identify potential pathogenic mutations, DSBs were induced by mitomycin C (MMC), and the DNA repair capacity was evaluated by the histone H2AX phosphorylation level. Two novel mutations of MCM8, i.e., c.724T>C (p.C242R) and c.1334C>A (p.S445*), were identified in a 13-year-old girl with POI who exhibited disappeared bilateral ovaries and short stature (height standard difference score [HtSDS] = -3.05), and her sister (aged 6 years and 7 months) with progressive POI whose ovary size decreased from normal to unclear and height growth gradually slowed. In the functional experiments, compared with the wild-type, HeLa cells overexpressing mutant p.C242R and p.S445* showed a higher sensitivity to MMC. Furthermore, the mutant p.S445* has a more deleterious effect on DNA damage repair. Our results reveal that affected children with the novel pathogenetic mutations p.C242R and p.S445* in the MCM8 gene are characterized by POI, short stature, cancer susceptibility, and genomic instability.//////////////////
|