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Previous studies found incomplete sperm FSs and abnormal flagella in Akap4 knockout mice. Meanwhile, it was reported that the partial deletion in AKAP4 is highly relevant to the dysplasia of the FS in an infertile man, and so far, there is no report about male infertility caused by hemizygous AKAP4 variant. Furthermore, the specific mechanisms of how the variant is relevant to the phenotype remain elusive. In this study, we investigated three multiple morphological abnormalities of the sperm flagella-affected men from three independent families (including one consanguine family) carried hemizygous c.C1285T variant in AKAP4. The patients carried this variant, which showed dysplastic sperm FS, and the protein expression of AKAP4 was decreased in flagella, which was further confirmed in HEK-293T cells in vitro. In addition, the co-localization and interaction between AKAP4 and glutamine-rich protein 2 (QRICH2) on the molecular level were identified by immunofluorescence and co-immunoprecipitation (CO-IP). The hemizygous c.1285C\u2009&amp;gt;\u2009T variant in AKAP4 induced decreased protein expression of QRICH2 in spermatozoa. These results suggested that the normal expression of AKAP4 is required for maintaining the expression of QRICH2 and the decreased protein expression of AKAP4 and QRICH2\uff0cas well as the interaction between them induced by the hemizygous variant of AKAP4 caused dysplastic fibrous sheath, which eventually led to reduced sperm motility and male infertility.<\/jats:p>","DOI":"10.1093\/hmg\/ddab234","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T11:22:47Z","timestamp":1628680967000},"page":"219-231","source":"Crossref","is-referenced-by-count":42,"title":["Loss-of-function missense variant of<i>AKAP4<\/i>induced male infertility through reduced interaction with QRICH2 during sperm flagella development"],"prefix":"10.1093","volume":"31","author":[{"given":"Guohui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaofeng","family":"Tu","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanlan","family":"Meng","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqiu","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxiu","family":"Lu","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinpeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, 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Lessons from Chlamydomonas reinhardtii","volume":"127","author":"Silflow","year":"2001","journal-title":"Plant Physiol."},{"key":"2022010913474043200_ref5","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1093\/molehr\/gau097","article-title":"Tssk4 is essential for maintaining the structural integrity of sperm flagellum","volume":"21","author":"Wang","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"2022010913474043200_ref6","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1095\/biolreprod.112.105262","article-title":"Loss of R2D2 proteins ROPN1 and ROPN1L causes defects in murine sperm motility, phosphorylation, and fibrous sheath integrity","volume":"88","author":"Fiedler","year":"2013","journal-title":"Biol. 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