Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. Qin Y et al. ABSTRACT: BACKGROUND: : Premature ovarian failure (POF) is a complex and heterogeneous disorder that is influenced by multiple genetic components. Numerous candidate gene studies designed to identify POF susceptibility loci have been published, but most positive findings have not been confirmed in follow up studies. We sought to determine if sequence variants previously associated with age at natural menopause (AANM) or early menopause (EM) contribute as well to genetic susceptibility to POF. METHOD: S: Our study was performed on 371 unrelated idiopathic POF patients and 800 female controls, all Chinese Han. Thirty six SNPs from previous genome-wide association studies (GWAS) responsible for AANM or EM and 3 additional SNPs in ESR1, and 2 additional SNPs in PTHB1 were tested using the Sequenom MassARRAY iPLEX platform for genotyping. RESULTS: : Three SNPs rs2278493 in HK3, rs2234693 in ESR1 and rs12611091 in BRSK1 showed nominally significant association with POF. Thus, a plausible relationship could exist between ESR1, BRSK1, HK3 and POF. CONCLUSIONS: : This largest association study undertaken to determine correlation between POF and AANM / EM revealed three significant SNPs (rs2278493, rs2234693, and rs12611091). All are associated with not only AAWM and EM but also POF. Insights into shared genetic susceptibility between POF and AANM/EM will provide novel entry points for unraveling genetic mechanism involved in ovarian reserve and oocyte aging processes.

Species: mouse
Mutation name: None
type: null mutation
fertility: embryonic lethal
Comment: Mammalian SAD kinases are required for neuronal polarization. Kishi M 2005 et al. Electrical activity in neurons is generally initiated in dendritic processes then propagated along axons to synapses, where it is passed to other neurons. Major structural features of neurons-their dendrites and axons-are thus related to their fundamental functions: the receipt and transmission of information. The acquisition of these distinct properties by dendrites and axons, called polarization, is a critical step in neuronal differentiation. We show here that SAD-A and SAD-B, mammalian orthologs of a kinase needed for presynaptic differentiation in Caenorhabditis elegans, are required for neuronal polarization. These kinases will provide entry points for unraveling signaling mechanisms that polarize neurons.Mice homozygous for deletion of only 1 gene were healthy and fertile, but double-knockout pups showed little spontaneous movement, were only weakly responsive to tactile stimulation, and died within 2 hours of birth. At embryonic day 19, principal divisions of brain, spinal cord, and peripheral nervous system had formed, but the forebrain was noticeably smaller in double-mutant embryos than in littermate controls. /////////////////////////

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Replication of loci influencing ages at menarche and menopause in Hispanic women: the Women's Health Initiative SHARe Study. Chen CT 2012 et al. Several genome-wide studies have identified loci associated with reproductive traits, such as ages of menarche and menopause, in women of European ancestry. In this study, we investigated the relevance of these loci in minority US Hispanic women. We utilized data from 3468 women who were genotyped as a part of the Women's Health Initiative SNP Health Association Resource. We replicated associations of eight loci (LRP18, LIN28B, CENPW, INHBA, TMEM38B, ZNF483, NFAT5 and OLFM2) with age at menarche, and of two loci (MCM8 and BRSK1/TMEM150B) with age at menopause. The MCM8 locus was also associated with early menopause risk. Three loci (CENPW, MCM8 and BRSK1/TMEM150B) were associated with the length of reproductive lifespan. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in minority US Hispanic women. /////////////////////////

Species: mouse
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Genetic insights into biological mechanisms governing human ovarian ageing. Ruth KS et al. (2021) Reproductive longevity is essential for fertility and influences healthy ageing in women^1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations³. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.////////////////// Earlier research showed that feeding pregnant mice a high-fat, high-sugar diet results in their female offspring having a lowered reproductive potential (reduced ovarian reserve)11. Ruth et al. observed changes in the expression of 2 of 35 assessed DRR-related genes (Dmc1 and Brsk1) in ovarian tissue from the female offspring of mice on this diet, suggesting that maternal diet can affect DNA repair in offspring.