{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:30Z","timestamp":1786121370766,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"crossref","award":["NSTC 111-2320-B-030 -007-MY3"],"award-info":[{"award-number":["NSTC 111-2320-B-030 -007-MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005866","name":"Far Eastern Memorial Hospital","doi-asserted-by":"publisher","award":["113-FEMH-FJU-01"],"award-info":[{"award-number":["113-FEMH-FJU-01"]}],"id":[{"id":"10.13039\/501100005866","id-type":"DOI","asserted-by":"publisher"}]},{"award":["113-FEMH-FJU-01"],"award-info":[{"award-number":["113-FEMH-FJU-01"]}],"id":[{"id":"https:\/\/ror.org\/019tq3436","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Male factors account for approximately 30\u201350% of subfertile couples. Teratozoospermia is one of the major causes of male infertility; however, the genetic factors underlying many cases remain incompletely understood. This study aimed to identify potential genetic variants associated with teratozoospermia and to investigate the possible involvement of Caudal-Type Homeobox 4 (CDX4) in sperm morphogenesis. Materials and Methods: Whole-exome sequencing was performed in 44 individuals with teratozoospermia. A rare CDX4 variant (NM_005193.2, c.103G&gt;T; NP_005184.1, Gly35Cys) was identified and confirmed by Sanger sequencing. Because CDX4 is located on the X chromosome, this variant was interpreted as hemizygous in the male patient. Sperm morphology, CDX4 localization, public GEO transcriptomic data (GSE6969), and CDX4 expression during murine spermiogenesis were analyzed. Results: The CDX4 p.Gly35Cys variant is located within the Caudal-like transactivation domain, a conserved region involved in transcriptional regulation. Spermatozoa from the patient carrying this variant exhibited severe morphological abnormalities, predominantly involving sperm-head defects, together with aberrant CDX4 localization along the midpiece and tail, in contrast to the neck- and annulus-enriched distribution observed in control spermatozoa. Reanalysis of the GEO dataset showed increased CDX4 transcript levels in teratozoospermic samples compared with normozoospermic controls. During murine spermiogenesis, CDX4 was detected in the nuclei of spermatogonia and spermatocytes and subsequently localized to the sperm head and neck\/tail regions during sperm morphogenesis. Conclusions: CDX4 c.103G&gt;T (p.Gly35Cys) is a rare hemizygous X-linked candidate variant associated with severe teratozoospermia in a single patient. Further cohort-based, segregation, and functional studies are required to clarify its role in sperm morphogenesis.<\/jats:p>","DOI":"10.3390\/medicina62081508","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:16:29Z","timestamp":1785935789000},"page":"1508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Hemizygous CDX4 Missense Variant Identified in a Taiwanese Man with Severe Teratozoospermia"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-2070","authenticated-orcid":false,"given":"Chin-Fong","family":"Au","sequence":"first","affiliation":[{"name":"Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan"},{"name":"PhD Program in Nutrition & Food Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6160-7816","authenticated-orcid":false,"given":"Tsung-Hsuan","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 106438, Taiwan"},{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chying-Chyuan","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taipei City Hospital, Zhongxing Branch and Branch for Women and Children, Taipei 103212, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Chun","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Urology, En Chu Kong Hospital, New Taipei City 237414, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiu-Dong","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan"},{"name":"Department of Nursing, College of Healthcare & Management, and General Education Center, Asia Eastern University of Science and Technology, New Taipei City 220303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1574-1579","authenticated-orcid":false,"given":"Ying-Hung","family":"Lin","sequence":"additional","affiliation":[{"name":"PhD Program in Nutrition & Food Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan"},{"name":"Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan"},{"name":"Center for Health Research and Innovation, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mascarenhas, M.N., Flaxman, S.R., Boerma, T., Vanderpoel, S., and Stevens, G.A. (2012). National, regional, and global trends in infertility prevalence since 1990: A systematic analysis of 277 health surveys. PLoS Med., 9.","DOI":"10.1371\/journal.pmed.1001356"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12958-015-0032-1","article-title":"A unique view on male infertility around the globe","volume":"13","author":"Agarwal","year":"2015","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0140-6736(20)32667-2","article-title":"Male infertility","volume":"397","author":"Agarwal","year":"2021","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1007\/s43032-023-01401-x","article-title":"Etiology of Male Infertility: An Update","volume":"31","author":"Bhattacharya","year":"2024","journal-title":"Reprod. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s10815-015-0433-2","article-title":"Genetic aspects of monomorphic teratozoospermia: A review","volume":"32","author":"Nguyen","year":"2015","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1007\/s10815-024-03274-8","article-title":"Genetic etiological spectrum of sperm morphological abnormalities","volume":"41","author":"Arora","year":"2024","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/humupd\/dmab030","article-title":"A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships","volume":"28","author":"Houston","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_8","doi-asserted-by":"crossref","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":"Coutton","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.ajhg.2013.07.009","article-title":"Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia","volume":"93","author":"Moore","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/humrep\/deab229","article-title":"Whole-exome sequencing of a cohort of infertile men reveals novel causative genes in teratozoospermia that are chiefly related to sperm head defects","volume":"37","author":"Li","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhou, H., Yin, Z., Ni, B., Lin, J., Luo, S., and Xie, W. (2024). Whole exome sequencing analysis of 167 men with primary infertility. BMC Med. Genom., 17.","DOI":"10.1186\/s12920-024-02005-3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1093\/humrep\/dez246","article-title":"Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia","volume":"35","author":"Oud","year":"2020","journal-title":"Hum. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e18031","DOI":"10.1111\/jcmm.18031","article-title":"Deleterious genetic changes in AGTPBP1 result in teratozoospermia with sperm head and flagella defects","volume":"28","author":"Lin","year":"2024","journal-title":"J. Cell Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19047","DOI":"10.1074\/jbc.M110.213983","article-title":"HoxA10 activates CDX4 transcription and Cdx4 activates HOXA10 transcription in myeloid cells","volume":"286","author":"Bei","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/324537a0","article-title":"A molecular gradient in early Drosophila embryos and its role in specifying the body pattern","volume":"324","author":"Macdonald","year":"1986","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/0092-8674(87)90197-8","article-title":"Expression of the caudal gene in the germ line of Drosophila: Formation of an RNA and protein gradient during early embryogenesis","volume":"48","author":"Mlodzik","year":"1987","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0070-2153(09)88008-3","article-title":"Hox, Cdx, and anteroposterior patterning in the mouse embryo","volume":"88","author":"Young","year":"2009","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1749-6632.2012.06625.x","article-title":"Caudal genes in blood development and leukemia","volume":"1266","author":"Lengerke","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1182\/bloodadvances.2019000761","article-title":"The ParaHox gene Cdx4 induces acute erythroid leukemia in mice","volume":"3","author":"Thoene","year":"2019","journal-title":"Blood Adv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1242\/dev.02216","article-title":"The Cdx4 mutation affects axial development and reveals an essential role of Cdx genes in the ontogenesis of the placental labyrinth in mice","volume":"133","author":"Lebrin","year":"2006","journal-title":"Development"},{"key":"ref_21","unstructured":"World Health Organization (2010). WHO Laboratory Manual for the Examination and Processing of Human Semen, World Health Organization. [5th ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.2353\/ajpath.2009.080955","article-title":"The expression level of septin12 is critical for spermiogenesis","volume":"174","author":"Lin","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/hmg\/ddm012","article-title":"Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs","volume":"16","author":"Platts","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1134\/S1022795424701023","article-title":"Genetic variants causing teratozoospermia in humans","volume":"60","author":"Kleshchev","year":"2024","journal-title":"Russ. J. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1134\/S1022795425700577","article-title":"Genetic Factors Contributing to the Development of Polymorphic Teratozoospermia in Humans","volume":"61","author":"Kleshchev","year":"2025","journal-title":"Russ. J. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","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":"ref_27","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1093\/humupd\/dmac002","article-title":"Transcriptional control of human gametogenesis","volume":"28","author":"Fang","year":"2022","journal-title":"Hum. Reprod. Update"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8090","DOI":"10.1073\/pnas.0601083103","article-title":"Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8","volume":"103","author":"Pangas","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1002\/humu.21264","article-title":"Mutations in SOHLH1 gene associate with nonobstructive azoospermia","volume":"31","author":"Choi","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/hmg\/ddab242","article-title":"The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition","volume":"31","author":"Liu","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16924","DOI":"10.1073\/pnas.0604579103","article-title":"Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model","volume":"103","author":"Bansal","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Le Beulze, M., Daubech, C., Balde-Camara, A., Ghieh, F., and Vialard, F. (2023). Mammal Reproductive Homeobox (Rhox) Genes: An Update of Their Involvement in Reproduction and Development. Genes, 14.","DOI":"10.3390\/genes14091685"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cell.2004.12.022","article-title":"Rhox: A new homeobox gene cluster","volume":"120","author":"Maclean","year":"2005","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lin, Y.H., Wang, Y.Y., Chen, H.I., Kuo, Y.C., Chiou, Y.W., Lin, H.H., Wu, C.M., Hsu, C.C., Chiang, H.S., and Kuo, P.L. (2012). SEPTIN12 genetic variants confer susceptibility to teratozoospermia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034011"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, Y.Y., Lai, T.H., Chen, M.F., Lee, H.L., Kuo, P.L., and Lin, Y.H. (2019). SEPT14 Mutations and Teratozoospermia: Genetic Effects on Sperm Head Morphology and DNA Integrity. J. Clin. Med., 8.","DOI":"10.3390\/jcm8091297"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e70414","DOI":"10.1096\/fj.202402135R","article-title":"SEPT14 complexes maintain sperm morphogenesis and function","volume":"39","author":"Wang","year":"2025","journal-title":"FASEB J."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/8\/1508\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:32:44Z","timestamp":1786077164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/8\/1508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["medicina62081508"],"URL":"https:\/\/doi.org\/10.3390\/medicina62081508","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}