{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:16:18Z","timestamp":1788419778478,"version":"build-2803163510"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Severe sperm motility defects are an important cause of male infertility and are frequently associated with sperm flagellar abnormalities.\n                      <jats:italic>TTC29<\/jats:italic>\n                      encodes an evolutionarily conserved axonemal protein implicated in sperm flagellar assembly and motility, yet the pathogenic mechanisms of\n                      <jats:italic>TTC29<\/jats:italic>\n                      variants remain incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A Chinese man with total asthenozoospermia was investigated using whole-exome sequencing, Sanger sequencing, transmission electron microscopy, sperm immunofluorescence, and heterologous expression analysis in HEK293\u00a0T cells. The clinical outcome following intracytoplasmic sperm injection (ICSI) was also evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Whole-exome sequencing identified a novel\n                      <jats:italic>TTC29<\/jats:italic>\n                      frameshift variant (NM_031956.4:c.121dupA; p. Ile41Asnfs*21), which was confirmed by Sanger sequencing. Transmission electron microscopy revealed severe ultrastructural abnormalities involving both the midpiece and principal piece, with disruption of the canonical 9 + 2 axonemal architecture and marked abnormalities of peri-axonemal structures. In representative immunofluorescence images, TTC29 signal was readily detected along the sperm flagellum in the fertile control, whereas a visibly weaker signal was observed in spermatozoa from the proband. Heterologous expression analysis showed little or no detectable production of the expected TTC29 protein product from the mutant construct. Although fertilization was achieved following two ICSI cycles, no clinical pregnancy was obtained.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We identified a novel\n                      <jats:italic>TTC29<\/jats:italic>\n                      frameshift variant associated with total asthenozoospermia and male infertility. Genetic, ultrastructural, and heterologous expression evidence supports a deleterious effect of the identified\n                      <jats:italic>TTC29<\/jats:italic>\n                      variant, thereby expanding the mutational spectrum of\n                      <jats:italic>TTC29<\/jats:italic>\n                      -related infertility and providing further insight into the molecular basis of severe sperm motility disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1937470","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:47:01Z","timestamp":1788418021000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel frameshift variant in TTC29 associated with total asthenozoospermia and male infertility"],"prefix":"10.3389","volume":"14","author":[{"given":"Lingyi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine Center, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, Henan, China"]},{"name":"Department of Andrology, Jiaozuo Maternal and Child Health Hospital","place":["Jiaozuo, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqing","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Andrology, Jiaozuo Maternal and Child Health Hospital","place":["Jiaozuo, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Andrology, Jiaozuo Maternal and Child Health Hospital","place":["Jiaozuo, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Jiaozuo Maternal and Child Health Hospital","place":["Jiaozuo, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Jiaozuo Maternal and Child Health Hospital","place":["Jiaozuo, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baona","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Jiaozuo Maternal and Child Health Hospital","place":["Jiaozuo, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2872","DOI":"10.1093\/humrep\/dew262","article-title":"Whole-exome sequencing of familial cases of multiple morphological abnormalities of the sperm flagella (MMAF) reveals new DNAH1 mutations","volume":"31","author":"Amiri-Yekta","year":"2016","journal-title":"Hum. Reprod."},{"key":"B2","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.ajhg.2013.11.017","article-title":"Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to Male infertility from multiple morphological abnormalities of the sperm flagella","volume":"94","author":"Ben Khelifa","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1002\/(SICI)1521-1878(199911)21:11<932::AID-BIES5>3.0.CO;2-N","article-title":"The tetratricopeptide repeat: a structural motif mediating protein-protein interactions","volume":"21","author":"Blatch","year":"1999","journal-title":"Bioessays"},{"key":"B4","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1001\/jama.2021.4788","article-title":"Diagnosis and management of infertility: a review","volume":"326","author":"Carson","year":"2021","journal-title":"JAMA"},{"key":"B5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1146\/annurev.biochem.76.050106.093909","article-title":"The nonsense-mediated decay RNA surveillance pathway","volume":"76","author":"Chang","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"103765","DOI":"10.1016\/j.rbmo.2023.103765","article-title":"A novel homozygous nonsense variant of AK7 is associated with multiple morphological abnormalities of the sperm flagella","volume":"48","author":"Chang","year":"2024","journal-title":"Reprod. Biomed. Online"},{"key":"B7","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1093\/humupd\/dmv020","article-title":"Teratozoospermia: spotlight on the main genetic actors in the human","volume":"21","author":"Coutton","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"B8","doi-asserted-by":"publisher","first-page":"RP87698","DOI":"10.7554\/eLife.87698","article-title":"Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function","volume":"12","author":"Dacheux","year":"2023","journal-title":"Elife"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e2078","DOI":"10.1002\/mgg3.2078","article-title":"Novel biallelic mutations in TTC29 cause asthenoteratospermia and male infertility","volume":"10","author":"Dai","year":"2022","journal-title":"Molec Gen and Gen Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1016\/j.ajhg.2018.03.007","article-title":"Absence of CFAP69 causes Male infertility due to multiple morphological abnormalities of the flagella in human and mouse","volume":"102","author":"Dong","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2848","DOI":"10.1093\/humrep\/deab200","article-title":"Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum","volume":"36","author":"Ferreux","year":"2021","journal-title":"Hum. Reprod."},{"key":"B12","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1093\/molehr\/gar034","article-title":"Sperm flagella: comparative and phylogenetic perspectives of protein components","volume":"17","author":"Inaba","year":"2011","journal-title":"Mol. Hum. Reprod."},{"key":"B13","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.ajhg.2018.07.014","article-title":"A homozygous ancestral SVA-Insertion-Mediated deletion in WDR66 induces multiple morphological abnormalities of the sperm flagellum and Male infertility","volume":"103","author":"Kherraf","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/s41585-018-0003-3","article-title":"Genetics of male infertility","volume":"15","author":"Krausz","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1093\/biolre\/iox096","article-title":"Formation and function of sperm tail structures in association with sperm motility defects","volume":"97","author":"Lehti","year":"2017","journal-title":"Biol. Reprod."},{"key":"B16","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1136\/jmedgenet-2019-106344","article-title":"Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice","volume":"57","author":"Li","year":"2020","journal-title":"J. Med. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1016\/j.ajhg.2019.10.010","article-title":"Bi-allelic mutations in TTC29 cause Male subfertility with asthenoteratospermia in humans and mice","volume":"105","author":"Liu","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.ajhg.2019.02.020","article-title":"Bi-allelic mutations in TTC21A induce asthenoteratospermia in humans and mice","volume":"104","author":"Liu","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1377780","DOI":"10.3389\/fendo.2024.1377780","article-title":"Decreased embryo developmental potential and lower cumulative pregnancy rate in men with multiple morphological abnormalities of the sperm flagella","volume":"15","author":"Long","year":"2024","journal-title":"Front. Endocrinol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1016\/j.ajhg.2019.10.007","article-title":"Mutations in TTC29, encoding an evolutionarily conserved axonemal protein, result in asthenozoospermia and Male infertility","volume":"105","author":"Lor\u00e8s","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s12610-019-0083-9","article-title":"Genetic causes of male infertility: snapshot on morphological abnormalities of the sperm flagellum","volume":"29","author":"Nsota Mbango","year":"2019","journal-title":"Basic Clin. Androl."},{"key":"B22","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/0140-6736(92)92425-f","article-title":"Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte","volume":"340","author":"Palermo","year":"1992","journal-title":"Lancet"},{"key":"B23","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1146\/annurev.physiol.69.040705.141236","article-title":"Overview of structure and function of mammalian cilia","volume":"69","author":"Satir","year":"2007","journal-title":"Annu. Rev. Physiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1007\/s00018-019-03389-7","article-title":"Sperm defects in primary ciliary dyskinesia and related causes of Male infertility","volume":"77","author":"Sironen","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1016\/j.ajhg.2017.04.012","article-title":"Biallelic mutations in CFAP43 and CFAP44 cause Male infertility with multiple morphological abnormalities of the sperm flagella","volume":"100","author":"Tang","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"a028092","DOI":"10.1101\/cshperspect.a028092","article-title":"The intraflagellar transport machinery","volume":"8","author":"Taschner","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1093\/humrep\/dew083","article-title":"Patients with multiple morphological abnormalities of the sperm flagella due to DNAH1 mutations have a good prognosis following intracytoplasmic sperm injection","volume":"31","author":"Wambergue","year":"2016","journal-title":"Hum. Reprod."},{"key":"B29","doi-asserted-by":"publisher","first-page":"236","DOI":"10.4103\/aja.aja_53_19","article-title":"Insight on multiple morphological abnormalities of sperm flagella in male infertility: what is new?","volume":"22","author":"Wang","year":"2020","journal-title":"Asian J. Androl."},{"key":"B30","volume-title":"WHO Laboratory Manual for the Examination and Processing of Human Semen","year":"2010"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.3390\/genes15101315","article-title":"The molecular basis of multiple morphological abnormalities of sperm flagella and its impact on clinical practice","volume":"15","author":"Zhou","year":"2024","journal-title":"Genes"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1937470\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:47:02Z","timestamp":1788418022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1937470\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":31,"alternative-id":["10.3389\/fcell.2026.1937470"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1937470","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"article-number":"1937470"}}