ABSTRACT
Premature ovarian insufficiency (POI) is a heterogeneous disease affecting the physical and mental health of millions of women worldwide. The contribution of genetic factors in the pathogenesis of POI has increased, with quite a few of causative genes involved in meiosis. ZMM proteins are a group of conserved proteins participating in meiotic synapsis and crossover maturation. Here, by screening the variations of ZMM genes in our in-house WES database of 1030 idiopathic POI patients, one novel homozygous variation in SPO16 (c.160 + 8A > G) was firstly identified in one patient. The variation was verified to disturb mRNA splicing by minigene assay, produced a non-functional SPO16 protein, and was classified as pathogenetic according to American College of Medical Genetics guideline. During meiotic prophase I, SHOC1 binds to branched DNA and recruits SPO16 and other ZMM proteins to facilitate crossover formation. Together with our recent identified bi-allelic variations of SHOC1 in a published work, this study highlighted the essential roles of ZMM genes in the maintenance of ovarian function and expanded the POI gene spectrum.
Subject(s)
Meiosis , Primary Ovarian Insufficiency , Female , Humans , Crossing Over, Genetic , DNA , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Meiosis/genetics , Primary Ovarian Insufficiency/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolismABSTRACT
Meiosis is pivotal to gametogenesis and fertility. Meiotic recombination is a mandatory process that ensures faithful chromosome segregation and generates genetic diversity in gametes. Non-obstructive azoospermia (NOA) caused by meiotic arrest is a common cause of male infertility and has many genetic origins, including chromosome abnormalities, Y chromosome microdeletion and monogenic mutations. However, the genetic causes of the majority of NOA cases remain to be elucidated. Here, we report our findings of three Shortage in chiasmata 1 (SHOC1) bi-allelic variants in three NOA patients, of which two are homozygous for the same loss-of-function variant (c.231_232del: p.L78Sfs*9), and one is heterozygous for two different missense variants (c.1978G>A: p.A660T; c.4274G>A: p.R1425H). Testicular biopsy of one patient revealed impairment of spermatocyte maturation. Both germ-cell-specific and general Shoc1-knockout mice exhibited similar male infertility phenotypes. Subsequent analysis revealed comprehensive defects in homologous pairing and synapsis along with abnormal expression of DMC1, RAD51 and RPA2 in Shoc1-defective spermatocyte spreads. These findings imply that SHOC1 may have a presynaptic function during meiotic recombination apart from its previously identified role in crossover formation. Overall, our results provide strong evidence for the clinical relevance of SHOC1 mutations in patients with NOA and contribute to a deeper mechanistic understanding of the role of SHOC1 during meiotic recombination.
Subject(s)
Azoospermia , DNA-Binding Proteins , Infertility, Male , Meiosis , Animals , Azoospermia/genetics , Azoospermia/pathology , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Disease Models, Animal , Humans , Infertility, Male/genetics , Infertility, Male/pathology , Male , Meiosis/genetics , Mice , Mice, KnockoutABSTRACT
Meiosis is essential for eukaryotic sexual reproduction and plant fertility, and crossovers (COs) are essential for meiosis and the formation of new allelic combinations in gametes. In this study, we report the isolation of a meiotic gene, OsSHOC1, and the identification of its partner, OsPTD1. Osshoc1 was sterile both in male and female gametophytes, and it showed a striking reduction in the number of meiotic COs, indicating that OsSHOC1 was required for normal CO formation. Further investigations showed that OsSHOC1 physically interacted with OsPTD1 and that the latter was also required for normal CO formation and plant fertility. Additionally, the expression profiles of both genes were consistent with their functions. Our results suggest that OsSHOC1 and OsPTD1 are essential for rice fertility and CO formation, possibly by stabilizing the recombinant intermediates during meiosis.