MSH5 is a meiosis-specific MutS homolog that functions as a core component of the MutSγ (MSH4-MSH5) complex, essential for meiotic recombination and crossover formation 1. MSH5 binds branched recombination intermediates and directly stimulates the MLH1-MLH3 endonuclease to process Holliday junctions, facilitating reciprocal DNA exchange between homologous chr6 1. The protein is highly expressed in testis and thymus, with interactions with MSH4 protein demonstrated across eukaryotic species 2. MSH5 mutations cause severe reproductive dysfunction: pathogenic variants in MSH5 are associated with premature ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) 34. In NOA patients with MSH5 defects, all individuals showed unsuccessful sperm retrieval, indicating complete meiotic failure 4. Oligogenic variants combining MSH4 and MSH5 mutations associate with earlier POI onset and increased amenorrhea prevalence compared to monogenic defects 5. Transcriptionally, MSH5 expression is regulated by HSF5, a meiotic progression factor controlling crossover formation genes 6. These findings establish MSH5 as critical for successful meiosis and indicate genetic screening utility for infertility diagnosis.