Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Msh5-/- mice are viable but sterile (Edelmann et al. 1999). Meiosis in these mice is affected due to the disruption of chromosome pairing in prophase I. This meiotic failure leads to a diminution in testicular size and a complete loss of ovarian structures. The oocytes die shortly post-partum and follicular structure fail to form leading to degeneration of the ovary reminiscent of Turner?s syndrom in humans. These results show that normal Msh5 function is essential for meiotic progression and, in females, gonadal maintenance.

Species: C. elegans
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Kelly KO, et al reported that Caenorhabditis elegans msh-5 is required for both normal and radiation-induced meiotic crossing over but not for completion of meiosis. Crossing over and chiasma formation during Caenorhabditis elegans meiosis require msh-5, which encodes a conserved germline-specific MutS family member. msh-5 mutant oocytes lack chiasmata between homologous chromosomes, and crossover frequencies are severely reduced in both oocyte and spermatocyte meiosis. Artificially induced DNA breaks do not bypass the requirement for msh-5, suggesting that msh-5 functions after the initiation step of meiotic recombination. msh-5 mutants are apparently competent to repair breaks induced during meiosis, but accomplish repair in a way that does not lead to crossovers between homologs. These results combine with data from budding yeast to establish a conserved role for Msh5 proteins in promoting the crossover outcome of meiotic recombination events. Apart from the crossover deficit, progression through meiotic prophase is largely unperturbed in msh-5 mutants. Homologous chromosomes are fully aligned at the pachytene stage, and germ cells survive to complete meiosis and gametogenesis with high efficiency. Our demonstration that artificially induced breaks generate crossovers and chiasmata using the normal meiotic recombination machinery suggests (1) that association of breaks with a preinitiation complex is not a prerequisite for entering the meiotic recombination pathway and (2) that the decision for a subset of recombination events to become crossovers is made after the initiation step.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Caspase 9is constitutively activated in mouse oocytes and plays a key role in oocyte elimination during meiotic prophaseprogression. Ene AC et al. In many mammalian species, more than half of the initial oocyte population is eliminated by neonatal life, thus limiting the oocyte reserve for reproduction. The cause or mechanism of this major oocyte loss remains poorly understood. We examined the apoptotic pathway involved in oocyte elimination in wild-type mouse ovaries as well as in Msh5 -/- ovaries, in which all oocytes were eliminated due to a lack of double strand break repair. Immunoblot and immunofluorescence staining showed that an initiator caspase 9and an effector caspase 7were constitutively activated in almost all oocytes in fetal ovaries regardless of their genotypes. In caspase 9 -/- ovaries, the total number of oocytes remained high while that in wild-type ovaries steadily declined during ovarian development. Therefore, the activation of caspase 9was required for but did not immediately lead to oocyte demise. We found that XIAP, an endogenous inhibitor of apoptosis, was also abundant in oocytes during meiotic prophase progression. On the other hand, a cleaved form of PARP1, a target of effector caspases, was localized to the nuclei of a limited number of oocytes, and the frequency of cleaved PARP1-positive oocyte nuclei increased significantly higher before all oocytes disappeared in Msh5 -/- ovaries. We conclude that the mitochondrial apoptotic pathway mediated by caspase 9is constitutively activated in oocytes and renders the elimination of oocytes with meiotic errors, which can be captured by the cleavage ofPARP1.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Genetic investigation of four meiotic genes in women with premature ovarian failure. Mandon-Pépin B et al. (2008) The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). Case-control study. Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon.//////////////////

Species: human
Mutation name:
type: None
fertility: None
Comment: Mutations in MSH5 in primary ovarian insufficiency Ting Guo/2017 , Abstract Primary ovarian insufficiency (POI) is a genetically heterogeneous disorder that occurs in familial or sporadic fashion. Through whole exome sequencing in a Chinese pedigree with POI, we identified a novel homozygousmissensemutation (ENST00000375755: c.1459G>T, p.D487Y) in theMSH5 gene in two sisters with POI. The homologous mutation inmice resulted in atrophic ovaries without oocytes, and in vitro functional study revealed thatmutantMSH5 impaired DNA homologous recombination repair. From sanger sequencing of MSH5 in 200 sporadic POI patients, we identified three heterozygousmutations (ENST00000375755:c.1057C>A, p.L353M; c.1459G>T, p.D487Y and c.2107 A>G, p.I703V). Considering the heterozygous p.D487Y carrier in the POI pedigree was fertile, the causality of the three heterozygous mutations in POI needmore evidence. Our studies confirmed that perturbation of genes involved in DNA damage repair could lead to non-syndromic POI. The underlying mechanism-inability to repair DNA damage-will receive increasing attention with respect to POI.