{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:20:31Z","timestamp":1789539631978,"version":"build-2803163510"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Dysfunction of motile cilia, including respiratory cilia and sperm flagella, typically leads to primary ciliary dyskinesia and male infertility or low fertility in humans. Genetic defects of <jats:italic>LRRC6<\/jats:italic> have been associated with primary ciliary dyskinesia and asthenozoospermia due to abnormal ultrastructure of ciliated axonemes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To identify novel mutations of the <jats:italic>LRRC6<\/jats:italic> gene related to multiple morphological abnormalities of the sperm flagella and male infertility and investigate the underlying molecular mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>The <jats:italic>LRRC6<\/jats:italic> mutations were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning, and transmission electron microscopy were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Further tandem mass tagging proteomics analyses were performed to explore the effect of mutations and confirmed by immunostaining and western blotting. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic <jats:italic>LRRC6<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we identified a novel homozygous <jats:italic>LRRC6<\/jats:italic> mutation in a consanguineous family, characterized by asthenozoospermia and primary ciliary dyskinesia. Further Semen parameter and morphology analysis demonstrate that the novel <jats:italic>LRRC6<\/jats:italic> mutation leads to a significant reduction in sperm flagella length, a decrease in sperm progressive motility parameters, and abnormalities of sperm ultrastructure. Specifically, the absence of outer dynein arms and inner dynein arms, and incomplete mitochondrial sheath in the flagellar mid\u2010piece were observed by transmission electron microscopy. In addition, tandem mass tagging proteomics analysis revealed that spermatozoa obtained from patients harboring the <jats:italic>LRRC6<\/jats:italic> mutation exhibited a significant decrease in the expression levels of proteins related to the assembly and function of dynein axonemal arms. Functional analysis revealed that this novel <jats:italic>LRRC6<\/jats:italic> mutation disrupted the function of the leucine\u2010rich repeat containing 6 protein, which in turn affects the expression of the dynein arm proteins and leucine\u2010rich repeat containing 6\u2010interacting proteins CCDC40, SPAG1, and ZMYND10. Finally, we reported a successful pregnancy through assisted reproductive technology with intracytoplasmic sperm injection in the female partner of the proband.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and conclusion<\/jats:title><jats:p>This study highlights the identification of a novel homozygous <jats:italic>LRRC6<\/jats:italic> mutation in a consanguineous family and its impact on sperm progressive motility, morphology, and sperm kinetics parameters, which could facilitate the genetic diagnosis of asthenozoospermia and offer valuable perspectives for future genetic counseling endeavors.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.13685","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T12:58:14Z","timestamp":1719493094000},"page":"459-472","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A novel homozygous <i>LRRC6<\/i> mutation causes male infertility with asthenozoospermia and primary ciliary dyskinesia in humans"],"prefix":"10.1111","volume":"13","author":[{"given":"Shengjia","family":"Shi","sequence":"first","affiliation":[{"name":"Reproductive center Northwest Women's and Children's Hospital  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangrong","family":"Tang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering Center for Reproductive Medicine Women and Children's Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9758-859X","authenticated-orcid":false,"given":"Shunhua","family":"Long","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Human Embryo Engineering Center for Reproductive Medicine Women and Children's Hospital of Chongqing Medical University  Chongqing 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