The Escherichia coli MutHLS system has been highly conserved throughout evolution. The eukaryotic pathway results in a specialization of MutS homologs that have evolved to play crucial roles in both DNA mismatch repair and meiotic recombination. In Saccharomyces cerevisiae, MSH4 (MutS homolog 4) is a meiosis-specific protein that is not involved in mismatch correction. This protein is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. Paquis-Flucklinger et al identified the human MSH4 homolog gene. The predicted amino acid sequence shows 28.7% identity with the S. cerevisiae MSH4 protein.
NCBI Summary:
This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]
General function
Cell death/survival, DNA Replication
Comment
Eisen (1998) reported a phylogenomic study of the MutS family of proteins.
Cellular localization
Nuclear
Comment
Ovarian function
Germ cell development
Comment
Paquis- Flucklinger et al. (1997) reported that ,by Northern blot analysis, human MSH4 transcripts are only detectable in testis and in ovary with a lower level of expression.
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Follicle stages
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Kneitz B et al. Msh4 (MutS homolog 4) is a member of the mammalian mismatch repair gene family whose members are involved in postreplicative DNA mismatch repair as well as in the control of meiotic recombination. In this report we show that MSH4 has an essential role in the control of male and female meiosis. We demonstrate that MSH4 is present in the nuclei of spermatocytes early in prophase I and that it forms discrete foci along meiotic chromosomes during the zygotene and pachytene stages of meiosis. Disruption of the Msh4 gene in mice results in male and female sterility due to meiotic failure. Although meiosis is initiated in Msh4 mutant male and female mice, as indicated by the chromosomal localization of RAD51 and COR1 during leptonema/zygonema, the chromosomes fail to undergo normal pairing. Our results show that MSH4 localization on chromosomes during the early stages of meiosis is essential for normal chromosome synapsis in prophase I and that it acts in the same pathway as MSH5.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. Carlosama C et al. (2018) Premature ovarian insufficiency (POI) is a frequent pathology that affects women under 40 years of age, characterized by an early cessation of menses and high FSH levels. Despite recent progresses in molecular diagnosis, the etiology of POI remains idiopathic in most cases. Whole-exome sequencing of members of a Colombian family affected by POI allowed us to identify a novel homozygous donor splice-site mutation in the meiotic gene MSH4 (MutS Homolog 4). The variant followed a strict mendelian segregation within the family and was absent in a cohort of 135 women over 50 years of age without history of infertility, from the same geographical region as the affected family. Exon trapping experiments showed that the splice-site mutation induced skipping of exon 17. At the protein level, the mutation p.Ile743_Lys785del is predicted to lead to the ablation of the highly conserved Walker B motif of the ATP-binding domain, thus inactivating MSH4. Our study describes the first MSH4 mutation associated with POI and increases the number of meiotic/DNA repair genes formally implicated as being responsible for this condition.//////////////////