{"title":"Novel CYLC1 variants are associated with male infertility due to sperm head deformity.","authors":"Kexin Yu, Yu Wang, Xiaoya Zhu, Huan Wu, Yuying Jiao, Jingjing Zhang, Zongliu Duan, Yiru Zhou, Mingfei Xiang, Fengsong Wang, Xiaoyu Yang, Yunxia Cao, Fuxi Zhu","doi":"10.1007/s10815-025-03665-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To identify novel CYLC1 variants in infertile men with sperm head deformity.</p><p><strong>Methods: </strong>Two infertile men underwent routine semen analysis, followed by whole-exome sequencing (WES) and Sanger sequencing to identify candidate pathogenic variants. Morphologic characteristics of sperm were analyzed by Hematoxylin-eosin (HE) staining, while Western blotting and immunofluorescence staining were used to evaluate variant effects on protein expression and localization. A Cylc1 knockout (KO) mouse model, generated by CRISPR/Cas9, was subsequently analyzed. Sperm from Cylc1-KO mice were examined using HE staining, immunofluorescence, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) to evaluate morphological and ultrastructural features.</p><p><strong>Results: </strong>Two novel variants in CYLC1 (NM_021118.3: c.982A > G: p.K328E and c.971A > T: p.K324M) were identified in two infertile men with sperm head deformity. The CYLC1 variants had no significant effect on protein expression levels, but the localization of CYLC1 and the acrosome morphology of sperm from infertile men were altered. Notably, the localization of PLCZ1 was also altered in the sperm. Cylc1-KO mice displayed a similar subfertility phenotype, with ultrastructural analysis (SEM/TEM) demonstrating acrosome-nuclear detachment in sperm. Importantly, two infertile men achieved successful pregnancy outcomes through intracytoplasmic sperm injection (ICSI).</p><p><strong>Conclusions: </strong>Our results enrich the variant spectrum of CYLC1, offering additional support for an association between CYLC1 variants and male infertility.</p>","PeriodicalId":15246,"journal":{"name":"Journal of Assisted Reproduction and Genetics","volume":" ","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Assisted Reproduction and Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10815-025-03665-5","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: To identify novel CYLC1 variants in infertile men with sperm head deformity.
Methods: Two infertile men underwent routine semen analysis, followed by whole-exome sequencing (WES) and Sanger sequencing to identify candidate pathogenic variants. Morphologic characteristics of sperm were analyzed by Hematoxylin-eosin (HE) staining, while Western blotting and immunofluorescence staining were used to evaluate variant effects on protein expression and localization. A Cylc1 knockout (KO) mouse model, generated by CRISPR/Cas9, was subsequently analyzed. Sperm from Cylc1-KO mice were examined using HE staining, immunofluorescence, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) to evaluate morphological and ultrastructural features.
Results: Two novel variants in CYLC1 (NM_021118.3: c.982A > G: p.K328E and c.971A > T: p.K324M) were identified in two infertile men with sperm head deformity. The CYLC1 variants had no significant effect on protein expression levels, but the localization of CYLC1 and the acrosome morphology of sperm from infertile men were altered. Notably, the localization of PLCZ1 was also altered in the sperm. Cylc1-KO mice displayed a similar subfertility phenotype, with ultrastructural analysis (SEM/TEM) demonstrating acrosome-nuclear detachment in sperm. Importantly, two infertile men achieved successful pregnancy outcomes through intracytoplasmic sperm injection (ICSI).
Conclusions: Our results enrich the variant spectrum of CYLC1, offering additional support for an association between CYLC1 variants and male infertility.
期刊介绍：
The Journal of Assisted Reproduction and Genetics publishes cellular, molecular, genetic, and epigenetic discoveries advancing our understanding of the biology and underlying mechanisms from gametogenesis to offspring health. Special emphasis is placed on the practice and evolution of assisted reproduction technologies (ARTs) with reference to the diagnosis and management of diseases affecting fertility. Our goal is to educate our readership in the translation of basic and clinical discoveries made from human or relevant animal models to the safe and efficacious practice of human ARTs. The scientific rigor and ethical standards embraced by the JARG editorial team ensures a broad international base of expertise guiding the marriage of contemporary clinical research paradigms with basic science discovery. JARG publishes original papers, minireviews, case reports, and opinion pieces often combined into special topic issues that will educate clinicians and scientists with interests in the mechanisms of human development that bear on the treatment of infertility and emerging innovations in human ARTs. The guiding principles of male and female reproductive health impacting pre- and post-conceptional viability and developmental potential are emphasized within the purview of human reproductive health in current and future generations of our species.
The journal is published in cooperation with the American Society for Reproductive Medicine, an organization of more than 8,000 physicians, researchers, nurses, technicians and other professionals dedicated to advancing knowledge and expertise in reproductive biology.
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