{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T20:54:14Z","timestamp":1793220854951,"version":"4.5.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"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. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The radial spoke head component 4A (<jats:italic>RSPH4A<\/jats:italic>) is involved in the assembly of radial spokes, which is essential for motile cilia function. Asthenoteratozoospermia in primary ciliary dyskinesia (PCD) related to <jats:italic>RSPH4A<\/jats:italic> variants has not been reported.<\/jats:p><jats:p><jats:bold>Materials and Methods:<\/jats:bold><jats:italic>RSPH4A<\/jats:italic> variants were identified and validated using whole-exome and Sanger sequencing in three unrelated Chinese families. High-speed video microscopy analysis (HSVA) was performed to measure the beating frequency and pattern of nasal cilia of the patients and healthy control. Papanicolaou staining and computer-aided sperm analysis were performed to analyze the morphology and motility of the sperm in patient 1. Immunofluorescence was adopted to confirm the structure deficiency of sperm and nasal cilia.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Patient 1 from family 1 is a 22-year-old unmarried male presented with bronchiectasis. Semen analysis and sperm Papanicolaou staining confirmed asthenoteratozoospermia. Novel compound heterozygous <jats:italic>RSPH4A<\/jats:italic> variants c.2T&amp;gt;C, p.(Met1Thr) and c.1774_1775del, p.(Leu592Aspfs*5) were detected in this patient. Patients 2 and 3 are from two unrelated consanguineous families; they are both females and exhibited bronchiectasis and infertility. Two homozygous <jats:italic>RSPH4A<\/jats:italic> variants c.2T&amp;gt;C, p.(Met1Thr) and c.351dupT, p.(Pro118Serfs*2) were detected, respectively. HSVA showed that most of the cilia in patients 1 and 3 were with abnormal rotational movement. The absence of RSPH4A and RSPH1 in patient 1\u2019s sperm and patient 3\u2019s respiratory cilia was indicated by immunofluorescence. Patient 2 died of pulmonary infection and respiratory failure at the age of 35 during follow-up.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Dysfunctional sperm flagellum and motile cilia in the respiratory tract and the fallopian tube were found in patients with <jats:italic>RSPH4A<\/jats:italic> variants. Our study enriches the genetic spectrum and clinical phenotypes of <jats:italic>RSPH4A<\/jats:italic> variants in PCD, and c.2T&amp;gt;C, p.(Met1Thr) detected in our patients may be a hotspot <jats:italic>RSPH4A<\/jats:italic> variant in Chinese.<\/jats:p>","DOI":"10.3389\/fgene.2022.922287","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T06:13:31Z","timestamp":1655878411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Novel RSPH4A Variants Associated With Primary Ciliary Dyskinesia\u2013Related Infertility in Three Chinese Families"],"prefix":"10.3389","volume":"13","author":[{"given":"Lin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongchun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danhui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1126\/science.1084576","article-title":"A Human Syndrome Caused by Immotile Cilia","volume":"193","author":"Afzelius","year":"1976","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1093\/humrep\/dev251","article-title":"Another Look at Human Sperm Morphology","volume":"31","author":"Auger","year":"2016","journal-title":"Hum. Reprod."},{"key":"B3","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":"B4","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1007\/s11684-021-0860-7","article-title":"Case Report of Neurofibromatosis Type 1 Combined with Primary Ciliary Dyskinesia","volume":"15","author":"Bian","year":"2021","journal-title":"Front. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1001\/jama.2021.4788","article-title":"Diagnosis and Management of Infertility","volume":"326","author":"Carson","year":"2021","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/ejhg.2014.79","article-title":"Unexpected Genetic Heterogeneity for Primary Ciliary Dyskinesia in the Irish Traveller Population","volume":"23","author":"Casey","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.ajhg.2009.01.011","article-title":"Mutations in Radial Spoke Head Protein Genes RSPH9 and RSPH4A Cause Primary Ciliary Dyskinesia with Central-Microtubular-Pair Abnormalities","volume":"84","author":"Castleman","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1183\/09031936.00088614","article-title":"Nasal Nitric Oxide Screening for Primary Ciliary Dyskinesia: Systematic Review and Meta-Analysis","volume":"44","author":"Collins","year":"2014","journal-title":"Eur. Respir. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1093\/humupd\/dmp048","article-title":"World Health Organization Reference Values for Human Semen Characteristics*\u2021","volume":"16","author":"Cooper","year":"2010","journal-title":"Hum. Reprod. update"},{"key":"B10","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/s41436-018-0064-y","article-title":"ZP2 Pathogenic Variants Cause In Vitro Fertilization Failure and Female Infertility","volume":"21","author":"Dai","year":"2019","journal-title":"Genet. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1002\/humu.22371","article-title":"Founder Mutation inRSPH4AIdentified in Patients of Hispanic Descent with Primary Ciliary Dyskinesia","volume":"34","author":"Daniels","year":"2013","journal-title":"Hum. Mutat."},{"key":"B12","doi-asserted-by":"publisher","first-page":"281","DOI":"10.3390\/diagnostics11020281","article-title":"Primary Ciliary Dyskinesia Diagnostic Challenges: Understanding the Clinical Phenotype of the Puerto Rican Founder Mutation","volume":"11","author":"De Jes\u00fas-Rojas","year":"2021","journal-title":"Diagn. Base"},{"key":"B13","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1002\/ppul.24583","article-title":"Genotype and Phenotype Evaluation of Patients with Primary Ciliary Dyskinesia: First Results from Turkey","volume":"55","author":"Emiralio\u011flu","year":"2020","journal-title":"Pediatr. Pulmonol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1165\/rcmb.2014-0483oc","article-title":"Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects","volume":"53","author":"Frommer","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1183\/13993003.00736-2016","article-title":"Clinical Manifestations in Primary Ciliary Dyskinesia: Systematic Review and Meta-Analysis","volume":"48","author":"Goutaki","year":"2016","journal-title":"Eur. Respir. J."},{"key":"B16","doi-asserted-by":"publisher","first-page":"7905","DOI":"10.1038\/s41598-017-08510-z","article-title":"An Effective Combination of Whole-Exome Sequencing and Runs of Homozygosity for the Diagnosis of Primary Ciliary Dyskinesia in Consanguineous Families","volume":"7","author":"Guo","year":"2017","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3984","DOI":"10.1096\/fj.201701359r","article-title":"Radial Spoke Proteins Regulate Otolith Formation during Early Zebrafish Development","volume":"32","author":"Han","year":"2018","journal-title":"FASEB J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.ajhg.2015.05.004","article-title":"RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes","volume":"97","author":"Jeanson","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1164\/rccm.201311-2047oc","article-title":"Mutations inRSPH1Cause Primary Ciliary Dyskinesia with a Unique Clinical and Ciliary Phenotype","volume":"189","author":"Knowles","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/s10038-021-00985-z","article-title":"DRC1 Deficiency Caused Primary Ciliary Dyskinesia and MMAF in a Chinese Patient","volume":"67","author":"Lei","year":"2022","journal-title":"J. Hum. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and Accurate Long-Read Alignment with Burrows-Wheeler Transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinforma. Oxf. Engl."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1601090","DOI":"10.1183\/13993003.01090-2016","article-title":"European Respiratory Society Guidelines for the Diagnosis of Primary Ciliary Dyskinesia","volume":"49","author":"Lucas","year":"2017","journal-title":"Eur. Respir. J."},{"key":"B24","doi-asserted-by":"publisher","first-page":"135","DOI":"10.3389\/fped.2017.00135","article-title":"Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies","volume":"5","author":"Mirra","year":"2017","journal-title":"Front. Pediatr."},{"key":"B25","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1111\/j.1469-1809.2009.00559.x","article-title":"Founder Mutation(s) in theRSPH9Gene Leading to Primary Ciliary Dyskinesia in Two Inbred Bedouin Families","volume":"74","author":"Reish","year":"2010","journal-title":"Ann. Hum. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1183\/23120541.00792-2020","article-title":"CiliarMove: New Software for Evaluating Ciliary Beat Frequency Helps Find Novel Mutations by a Portuguese Multidisciplinary Team on Primary Ciliary Dyskinesia","volume":"7","author":"Sampaio","year":"2021","journal-title":"ERJ Open Res."},{"key":"B27","first-page":"103","article-title":"A Complement for the WHO Laboratory Manual for the Examination and Processing of Human Semen (First Edition","volume":"23","author":"S\u00e1nchez-\u00c1lvarez","year":"2010","journal-title":"EJIFCC"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e13463","DOI":"10.1111\/and.13463","article-title":"Asthenozoospermia: Cellular and Molecular Contributing Factors and Treatment Strategies","volume":"52","author":"Shahrokhi","year":"2020","journal-title":"Andrologia"},{"key":"B29","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.devcel.2015.10.001","article-title":"Absence of Radial Spokes in Mouse Node Cilia Is Required for Rotational Movement but Confers Ultrastructural Instability as a Trade-Off","volume":"35","author":"Shinohara","year":"2015","journal-title":"Dev. Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/cm.10155","article-title":"The Radial Spokes and Central Apparatus: Mechano-Chemical Transducers that Regulate Flagellar Motility","volume":"57","author":"Smith","year":"2004","journal-title":"Cell Motil. Cytoskelet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ Data to High Confidence Variant Calls: the Genome Analysis Toolkit Best Practices Pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr. Protoc. Bioinforma."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1750314","DOI":"10.1183\/13993003.50314-2017","article-title":"\"Infertility in an Adult Cohort with Primary Ciliary Dyskinesia: Phenotype-Gene association.\" Gert Jan Vanaken, Laurence Bassinet, Mieke Boon, Rahma Mani, Isabelle Honor\u00e9, Jean-Francois Papon, Harry Cuppens, Martine Jaspers, Natalie Lorent, Andr\u00e9 Coste, Estelle Escudier, Serge Amselem, Bernard Maitre, Marie Legendre and Sophie Christin-Maitre. Eur Respir J 2017; 50: 1700314","volume":"50","author":"Vanaken","year":"2017","journal-title":"Eur. Respir. J."},{"key":"B33","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41572-020-0209-6","article-title":"Motile Ciliopathies","volume":"6","author":"Wallmeier","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional Annotation of Genetic Variants from High-Throughput Sequencing Data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1242\/jcs.02811","article-title":"Radial Spoke Proteins of Chlamydomonas Flagella","volume":"119","author":"Yang","year":"2006","journal-title":"J. Cell Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e1008664","DOI":"10.1371\/journal.pgen.1008664","article-title":"Rsph4a Is Essential for the Triplet Radial Spoke Head Assembly of the Mouse Motile Cilia","volume":"16","author":"Yoke","year":"2020","journal-title":"PLoS Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e2102940118","DOI":"10.1073\/pnas.2102940118","article-title":"Oviductal Motile Cilia Are Essential for Oocyte Pickup but Dispensable for Sperm and Embryo Transport","volume":"118","author":"Yuan","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"jcs259381","DOI":"10.1242\/jcs.259381","article-title":"LRRC23 Is a Conserved Component of the Radial Spoke that Is Necessary for Sperm Motility and Male Fertility in Mice","volume":"134","author":"Zhang","year":"2021","journal-title":"J. Cell Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e33667","DOI":"10.1371\/journal.pone.0033667","article-title":"Mutations in Radial Spoke Head Genes and Ultrastructural Cilia Defects in East-European Cohort of Primary Ciliary Dyskinesia Patients","volume":"7","author":"Zi\u0119tkiewicz","year":"2012","journal-title":"PloS One"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.922287\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T06:13:34Z","timestamp":1655878414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.922287\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":38,"alternative-id":["10.3389\/fgene.2022.922287"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.922287","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]},"article-number":"922287"}}