Reproductive aging and MCM8/9

Inherited defects in DNA repair are rare genetic conditions characterized by hypersensitivity to endogenous and exogenous DNA damage. Double-strand break (DSB) is the most severe form of DNA damage which can induce gross chromosomal rearrangements such as translocations, deletions, duplications, and complex genomic aberrations, triggering permanent cell cycle arrest and, ultimately, the death or malignant transformation of the affected cells. Hereditary defects in cellular DNA repair processes cause syndromic recessive conditions such as Fanconi anemia, Ataxia-telangiectasia, Bloom syndrome, Werner, and Xeroderma pigmentosum. Mutations in DSB repair genes have pleiotropic effects and are associated with growth retardation, skin, bone marrow, immune, nervous systems, and endocrine dysfunction as well as predisposition to cancers. Remarkably, the majority of the patients susceptible to chromosome breakage and genome instability also present with early gonadal dysfunction. We recently used whole exome sequencing to discover homozygous mutations in MCM8 or MCM9 genes in families whose members presented with absent or very small ovaries (ovarian dysgenesis) and chromosomal instability in somatic cells [1, 2]. Affected individuals in these families were diagnosed with hypergonadotropic (high follicle stimulating hormone levels) primary amenorrhea, hypothyroidism, growth retardation, and demonstrated a striking sensitivity to DNA cross-linking agents such as mitomycin C for both cultured fibroblasts and phytohaemagglutinin stimulated T-lymphocytes (Figure 1). The heterozygous mutation carriers appeared healthy and fertile, however they had an increased number of chromosome breakages in comparison to wildtype MCM8 and MCM9 individuals. None of the family members with homozygous mutations in MCM8 or MCM9 genes had cancer at the time of investigation, but all of them were premenopausal. Another group also reported additional families with homozygous mutations in MCM8 and gonadal dysgenesis [3]. Mice deficient in MCM8 or MCM9 are also infertile due to gonadal dysgenesis, are susceptible to chromosomal breakage, and develop ovarian tumors of unknown significance [4, 5] We don’t know whether humans with MCM8 or MCM9 mutations Commentary