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Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. MMAF phenotypes are understood to result from pathogenic variants of genes from multiple families including AKAP, DANI, DNAH, RSPH, CCDC, CFAP, TTC, and LRRC, among others. The Leucine-rich repeat protein (LRRC) family includes two members reported to cause MMAF phenotypes: Lrrc6 and Lrrc50. Despite vigorous research towards understanding the pathogenesis of MMAF-related diseases, many genes remain unknown underlying the flagellum biogenesis. Here, we found that Leucine-rich repeat containing 46 (LRRC46) is specifically expressed in the testes of adult mice, and show that LRRC46 is essential for sperm flagellum biogenesis. Both scanning electron microscopy (SEM) and Papanicolaou staining (PS) presents that the knockout of Lrrc46 in mice resulted in typical MMAF phenotypes, including sperm with short, coiled, and irregular flagella. The male KO mice had reduced total sperm counts, impaired sperm motility, and were completely infertile. No reproductive phenotypes were detected in Lrrc46\u2212\/\u2212 female mice. Immunofluorescence (IF) assays showed that LRRC46 was present throughout the entire flagella of control sperm, albeit with evident concentration at the mid-piece. Transmission electron microscopy (TEM) demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. About the important part of the Materials and Methods, SEM and PS were used to observe the typical MMAF-related irregular flagella morphological phenotypes, TEM was used to further inspect the sperm flagellum defects in ultrastructure, and IF was chosen to confirm the location of protein. Our study suggests that LRRC46 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with MMAF that causes male infertility. Thus, our study provides insights for understanding developmental processes underlying sperm flagellum formation and contribute to further observe the pathogenic genes that cause male infertility.<\/jats:p>","DOI":"10.3390\/ijms23158525","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T02:06:42Z","timestamp":1659319602000},"page":"8525","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse"],"prefix":"10.3390","volume":"23","author":[{"given":"Yingying","family":"Yin","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Jinan 250012, China"},{"name":"Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan 250012, China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Mu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Jinan 250012, China"},{"name":"Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan 250012, China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Jinan 250012, China"},{"name":"Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan 250012, China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan 250012, 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong University, Jinan 250012, China"},{"name":"Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan 250012, China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Lu","sequence":"additional","affiliation":[{"name":"CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9714-0936","authenticated-orcid":false,"given":"Wai-Yee","family":"Chan","sequence":"additional","affiliation":[{"name":"CUHK-SDU Joint Laboratory on Reproductive 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