{"id":6,"title":"Modeling of human MLH1 and MLH3 variants in mice reveals novel functions of MutLγ in meiotic DNA repair and the ovarian reserve","title_zh":"人MLH1与MLH3变异的小鼠模型揭示MutLγ在减数分裂DNA修复与卵巢储备中的新功能","url":"https://pubmed.ncbi.nlm.nih.gov/42990394","doi":"10.64898/2026.10.26.762008","pmid":"42990394","journal":"bioRxiv","kind":"paper","lang":"en","published_at":"2026-10-27T00:00:00+00:00","fetched_at":"2026-11-08T03:43:49+00:00","authors":["Ding X","Singh V","Schimenti JC"],"primary_topic":"oocyte","topics":[{"slug":"oocyte","score":13.0,"hits":["follicle","meiotic","oocyte","oocyte quality","ovarian","ovarian reserve","spindle"]},{"slug":"repro-endo","score":2.0,"hits":["poi","primary ovarian insufficiency"]},{"slug":"art-clinical","score":1.0,"hits":["infertility"]}],"topic_score":13.0,"preference_score":0.0,"preference_labels":[],"llm_score":80.0,"final_score":80.0,"score_dims":{"novelty":85,"rigor":75,"impact":78,"relevance":88,"translation":65},"recommend_reason":"该研究将MLH1/MLH3变异从传统交叉重组缺陷拓展到晚期前期I DNA过度切除与CHEK2依赖的卵母细胞质控，为POI和卵母细胞储备耗竭提供了新的机制解释；对生殖遗传咨询与后续功能验证有参考价值，但属预印本且以小鼠模型为主，尚需人源数据与同行评议。","keywords":["MutLγ","MLH1/MLH3","减数分裂DNA修复","卵巢储备","原发性卵巢功能不全","CHEK2"],"selected":1,"story_id":316,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-embryo-omics","source_name":"PubMed · 胚胎/卵母细胞组学","source_tier":1,"mention_count":3,"has_interpretation":false,"journal_key":"biorxiv","journal_tier":"standard","journal_if":null,"is_mock":false,"summary_zh":"该预印本研究在小鼠中构建多种人MLH1/MLH3错义与缺失等位基因模型，发现部分变异可独立于交换（CO）水平改变导致青春期前卵泡丢失；敲除DNA损伤检查点激酶Chek2可部分挽救Mlh1/Mlh3缺陷小鼠的卵母细胞池。精母细胞中可见晚期粗线期/双线期常染色体γH2AX异常“flare”，并伴随RPA及CtIP、RAD50、BLM等DNA末端加工因子的大灶，提示DNA过度切除。研究提出MutLγ可防止晚期前期I自发性DNA断裂或持续重组中间体的过度切除，并归纳MLH1/3变异通过CO严重丢失、亚阈值CO缺陷及晚期DNA加工异常三条通路损害生育力，后者经CHEK2依赖的卵母细胞质控耗竭卵巢储备，导致POI。","summary":"The mismatch repair proteins MLH1 and MLH3 form the MutLγ complex that is essential for >90% of meiotic crossovers (CO) in mice. Although deletion of either gene causes infertility, we previously found that mouse models of certain human MLH1/3 missense variants caused elevated aneuploidy and progressive loss of female fecundity despite having a normal ovarian reserve. Here, we report that additional missense and null alleles caused significant pre-pubertal follicle loss independent of alterations to meiotic CO levels. Deletion of the DNA damage checkpoint kinase Chek2 (Chk2) partially rescued the oocyte pool of Mlh1- and Mlh3 -deficient mice, indicating that defects in meiotic prophase I triggered oocyte elimination. In spermatocytes, both missense and null alleles caused abnormal γH2AX 'flares' on autosomes during late pachynema and diplonema, extending into chromatin loops from the synaptonemal complex. These flares frequently contained unusually large foci of the ssDNA binding protein RPA as well as DNA end processing factors including CtIP, RAD50 and BLM, consistent with abnormal and extensive DNA resection. The results reveal a previously unrecognized meiotic function of MutLγ in preventing DNA hyper-resection of spontaneous DNA breaks or of persistent recombination intermediates in late prophase I. Together with our previous studies, the results show that MLH1/3 variants can impair fertility through at least three mechanistically distinct routes: severe crossover loss sufficient to activate the metaphase I spindle assembly checkpoint; subthreshold crossover defects that increase aneuploidy and embryo loss; and abnormal late-prophase DNA processing that activates a CHEK2-dependent oocyte quality-control pathway and depletes the ovarian reserve, causing primary ovarian insufficiency (POI). Thus, MutLγ has broader roles in maintaining meiotic genome integrity than can be explained by crossover formation alone.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}