{"id":154,"title":"CT55 variants impair GABARAP-dependent autophagosome maturation to cause asthenoteratozoospermia in humans","title_zh":"CT55变异通过损害GABARAP依赖性自噬体成熟导致人类弱畸精子症","url":"https://pubmed.ncbi.nlm.nih.gov/42986183","doi":"10.1093/jmcb/mjag039","pmid":"42986183","journal":"J Mol Cell Biol","kind":"paper","lang":"en","published_at":"2026-11-05T00:00:00+00:00","fetched_at":"2026-11-08T03:43:57+00:00","authors":["Wang G","Zheng L","Ni X","Han B","Zhu W","Gao Y","Wu H","Hua R","He X"],"primary_topic":"male","topics":[{"slug":"male","score":4.0,"hits":["male infertility","sperm","spermatozoa","testis"]},{"slug":"art-clinical","score":1.0,"hits":["infertility"]},{"slug":"ethics-policy","score":1.0,"hits":["regulation"]}],"topic_score":4.0,"preference_score":0.0,"preference_labels":[],"llm_score":82.0,"final_score":82.0,"score_dims":{"novelty":80,"rigor":70,"impact":72,"relevance":88,"translation":62},"recommend_reason":"首次将CT55变异与GABARAP依赖性自噬体成熟缺陷及人类弱畸精子症联系起来，为男性不育的分子诊断与遗传咨询提供新基因-机制线索；但样本仅两例家系，机制证据以体外细胞验证为主，属中等力度证据。","keywords":["CT55","弱畸精子症","自噬体成熟","GABARAP","男性不育","遗传诊断"],"selected":1,"story_id":54,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-gametes","source_name":"PubMed · 配子与性腺","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":null,"journal_tier":"unknown","journal_if":null,"is_mock":false,"summary_zh":"研究在两例无亲缘关系的重度弱畸精子症（AST）男性中鉴定出两处新的半合子CT55变异：多外显子缺失截短变异（exon1_4del；p.Met1_Glu180del）与错义变异（c.433C>T；p.Pro145Ser）。结合超微结构、免疫荧光与生化分析，发现两变异以不同机制干扰CT55对GABARAP依赖性自噬体成熟的调控：截短型仍可与GABARAP结合但可能阻碍下游成熟，错义型则降低CT55表达并减弱CT55-GABARAP互作。患者精子表现为p62蓄积、LC3-II/LC3-I比值升高，以及顶体畸形、中段排列紊乱和轴丝不稳定等多区室重塑缺陷。结果支持CT55功能缺陷是Human AST的致病原因之一。","summary":"Asthenoteratozoospermia (AST) is a major cause of male infertility, yet the molecular connection between autophagy and sperm structural remodeling remains incompletely defined. Here, we identify two novel hemizygous cancer-testis antigen 55 (CT55) variants in unrelated men with severe AST: a multi-exonic truncation (exon1_4del; p.Met1_Glu180del) and a missense mutation (c.433C > T; p.Pro145Ser). Using integrated ultrastructural, immunofluorescence, and biochemical analyses, we show that these variants are associated with the altered CT55-mediated regulation of GABARAP-dependent autophagosome maturation through potentially distinct mechanisms. The truncating variant produces a shortened CT55 isoform that retains measurable GABARAP interaction but may impair downstream autophagosome maturation, whereas the missense variant reduces CT55 expression and weakens the CT55-GABARAP interaction in cell-based assays. Patient spermatozoa exhibit p62 accumulation, elevated LC3-II/LC3-I ratios, and broad cytoplasmic remodeling defects, including acrosomal malformation, midpiece disorganization, and axonemal instability. These findings support CT55 dysfunction as a cause of human AST and suggest that the disrupted CT55-associated autophagic regulation may contribute to multi-compartment sperm abnormalities. Our work expands the genetic and mechanistic framework of CT55-related male infertility and provides insights for molecular diagnosis and genetic counseling.","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}}