Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Mutant cohesin in premature ovarian failure. Caburet S 2014 et al. Premature ovarian failure is a major cause of female infertility. The genetic causes of this disorder remain unknown in most patients. Using whole-exome sequence analysis of a large consanguineous family with inherited premature ovarian failure, we identified a homozygous 1-bp deletion inducing a frameshift mutation in STAG3 on chromosome 7. STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion. Female mice devoid of Stag3 are sterile, and their fetal oocytes are arrested at early prophase I, leading to oocyte depletion at 1 week of age. /////////////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: STAG3-mediated stabilization of REC8 cohesin complexes promotes chromosome synapsis during meiosis. Fukuda T et al. (2014) Cohesion between sister chromatids in mitotic and meiotic cells is promoted by a ring-shaped protein structure, the cohesin complex. The cohesin core complex is composed of four subunits, including two structural maintenance of chromosome (SMC) proteins, one α-kleisin protein, and one SA protein. Meiotic cells express both mitotic and meiosis-specific cohesin core subunits, generating cohesin complexes with different subunit composition and possibly separate meiotic functions. Here, we have analyzed the in vivo function of STAG3, a vertebrate meiosis-specific SA protein. Mice with a hypomorphic allele of Stag3, which display a severely reduced level of STAG3, are viable but infertile. We show that meiocytes in homozygous mutant Stag3 mice display chromosome axis compaction, aberrant synapsis, impaired recombination and developmental arrest. We find that the three different α-kleisins present in meiotic cells show different dosage-dependent requirements for STAG3 and that STAG3-REC8 cohesin complexes have a critical role in supporting meiotic chromosome structure and functions.////////////////// Caburet et al. (2014) generated Stag3-null mice that had no overt phenotype apart from sterility in both males and females. Histologic analysis of whole ovaries of Stag3-null female mice at 1, 2, and 6 weeks of age showed a distinct lack of oocytes and ovarian follicles as well as dense stroma, indicating severe and very early ovarian dysgenesis. Analysis of oocytes from 15.5 to 19.5 gestational days showed that the axial elements did not progress beyond the leptotene stage in mutant oocytes, remaining very short rather than elongating to form the thin SYCP3 (604759) threads observed in late leptotene and zygotene wildtype oocytes. Immunolabeling of various meiotic cohesin subunits and SYCP3 in wildtype and Stag3-null fetal ovaries showed absent or very limited colocalization of other cohesins with SYCP3 in the mutant mice. Mutant oocytes also showed an obvious loss of centromeric sister chromatid cohesion. Caburet et al. (2014) concluded that STAG3 is essential for the formation of a functional cohesin ring and synaptonemal complex in mice and humans, and suggested that STAG3-containing cohesin complexes play a central role in maintenance of sister chromatid cohesion in mammalian oocytes.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Patiño LC et al. (2017) Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)? WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology. POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease. This is a retrospective cohort study performed on 69 women affected by POI. WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis. Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI. It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI. WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers. This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.//////////////////