{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:27:06Z","timestamp":1790749626439,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010425","name":"Tri-Service General Hospital","doi-asserted-by":"publisher","award":["TSGH-A-111012"],"award-info":[{"award-number":["TSGH-A-111012"]}],"id":[{"id":"10.13039\/501100010425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010425","name":"Tri-Service General Hospital","doi-asserted-by":"publisher","award":["TPCH-108-45"],"award-info":[{"award-number":["TPCH-108-45"]}],"id":[{"id":"10.13039\/501100010425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010425","name":"Tri-Service General Hospital","doi-asserted-by":"publisher","award":["MAB-109-032"],"award-info":[{"award-number":["MAB-109-032"]}],"id":[{"id":"10.13039\/501100010425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010425","name":"Tri-Service General Hospital","doi-asserted-by":"publisher","award":["MND-MAB-D-112153"],"award-info":[{"award-number":["MND-MAB-D-112153"]}],"id":[{"id":"10.13039\/501100010425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008904","name":"Taipei City Hospital","doi-asserted-by":"publisher","award":["TSGH-A-111012"],"award-info":[{"award-number":["TSGH-A-111012"]}],"id":[{"id":"10.13039\/100008904","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008904","name":"Taipei City Hospital","doi-asserted-by":"publisher","award":["TPCH-108-45"],"award-info":[{"award-number":["TPCH-108-45"]}],"id":[{"id":"10.13039\/100008904","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008904","name":"Taipei City Hospital","doi-asserted-by":"publisher","award":["MAB-109-032"],"award-info":[{"award-number":["MAB-109-032"]}],"id":[{"id":"10.13039\/100008904","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008904","name":"Taipei City Hospital","doi-asserted-by":"publisher","award":["MND-MAB-D-112153"],"award-info":[{"award-number":["MND-MAB-D-112153"]}],"id":[{"id":"10.13039\/100008904","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry National Defense Medical Affairs Bureau","award":["TSGH-A-111012"],"award-info":[{"award-number":["TSGH-A-111012"]}]},{"name":"Ministry National Defense Medical Affairs Bureau","award":["TPCH-108-45"],"award-info":[{"award-number":["TPCH-108-45"]}]},{"name":"Ministry National Defense Medical Affairs Bureau","award":["MAB-109-032"],"award-info":[{"award-number":["MAB-109-032"]}]},{"name":"Ministry National Defense Medical Affairs Bureau","award":["MND-MAB-D-112153"],"award-info":[{"award-number":["MND-MAB-D-112153"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Advanced reproductive technologies are utilized to identify the genetic mutations that lead to spermatogenic impairment, and allow informed genetic counseling to patients to prevent the transmission of genetic defects to offspring. The purpose of this study was to identify potential single nucleotide polymorphisms (SNPs) associated with male infertility. Genetic variants that may cause infertility are identified by combining the targeted next-generation sequencing (NGS) panel and whole exome sequencing (WES). The validation step of Sanger sequencing adds confidence to the identified variants. Our analysis revealed five distinct affected genes covering seven SNPs based on the targeted NGS panel and WES data: SPATA16 (rs16846616, 1515442, 1515441), CFTR (rs213950), KIF6 (rs2273063), STPG2 (r2903150), and DRC7 (rs3809611). Infertile men have a higher mutation rate than fertile men, especially those with azoospermia. These findings strongly support the hypothesis that the dysfunction of microtubule-related and spermatogenesis-specific genes contributes to idiopathic male infertility. The SPATA16, CFTR, KIF6, STPG2, and DRC7 mutations are associated with male infertility, specifically azoospermia, and a further examination of this genetic function is required.<\/jats:p>","DOI":"10.3390\/ijms242015363","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T07:15:36Z","timestamp":1697699736000},"page":"15363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Comprehensive Genetic Study of Microtubule-Associated Gene Clusters for Male Infertility in a Taiwanese Cohort"],"prefix":"10.3390","volume":"24","author":[{"given":"Chying-Chyuan","family":"Chan","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Taipei City Hospital-Renai Branch, Taipei 103212, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Te-Hsin","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taipei City Hospital-Renai Branch, Taipei 103212, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Chen","family":"Tseng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brang","family":"Mai","sequence":"additional","affiliation":[{"name":"School of Pharmacy, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Kuan","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Dentistry, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Liang","family":"Chou","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan"},{"name":"Department of Research and Development, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5360-8018","authenticated-orcid":false,"given":"Gwo-Jang","family":"Wu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan"},{"name":"Reproductive Medical Center, Department of Obstetrics and Gynecology, Tri-Service General Hospital, Taipei 114202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan"},{"name":"School of Pharmacy, National Defense Medical Center, Taipei 114201, Taiwan"},{"name":"Department of Research and Development, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"ref_1","first-page":"CD007411","article-title":"Antioxidants for male subfertility","volume":"3","author":"Smits","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/s10815-014-0280-6","article-title":"A multi-faceted approach to understanding male infertility: Gene mutations, molecular defects and assisted reproductive techniques (ART)","volume":"31","author":"Tahmasbpour","year":"2014","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5534\/wjmh.180066","article-title":"Microtubular Dysfunction and Male Infertility","volume":"38","author":"Gunes","year":"2020","journal-title":"World J. Men\u2019s Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.bbamcr.2011.10.009","article-title":"The mechanism of dynein motility: Insight from crystal structures of the motor domain","volume":"1823","author":"Cho","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R43","DOI":"10.1530\/REP-15-0310","article-title":"Formation and function of the manchette and flagellum during spermatogenesis","volume":"151","author":"Lehti","year":"2016","journal-title":"Reproduction"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/B978-0-12-407694-5.00003-1","article-title":"Interplay Between Spindle Architecture and Function","volume":"306","author":"Helmke","year":"2013","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.ydbio.2016.01.042","article-title":"Coiled-coil domain containing 42 (Ccdc42) is necessary for proper sperm development and male fertility in the mouse","volume":"412","author":"Pasek","year":"2016","journal-title":"Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ydbio.2006.10.004","article-title":"Compartmentalization of a unique ADP\/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece","volume":"302","author":"Kim","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"O\u2019Donnell, L., Rhodes, D., Smith, S.J., Merriner, D.J., Clark, B.J., Borg, C., Whittle, B., O\u2019Connor, A.E., Smith, L.B., and McNally, F.J. (2012). An Essential Role for Katanin p80 and Microtubule Severing in Male Gamete Production. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002698"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Smith, L.B., Milne, L., Nelson, N., Eddie, S., Brown, P., Atanassova, N., O\u2019Bryan, M.K., O\u2019Donnell, L., Rhodes, D., and Wells, S. (2012). KATNAL1 Regulation of Sertoli Cell Microtubule Dynamics Is Essential for Spermiogenesis and Male Fertility. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002697"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1111\/andr.13221","article-title":"Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility","volume":"10","author":"Garrido","year":"2022","journal-title":"Andrology"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wu, X., Yun, D., Sang, M., Liu, J., Zhou, L., Shi, J., Wang, L., Bu, T., Li, L., and Huang, Y. (2022). Defects of microtubule cytoskeletal organization in NOA human testes. Reprod. Biol. Endocrinol., 20.","DOI":"10.1186\/s12958-022-01026-w"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"765639","DOI":"10.3389\/fendo.2021.765639","article-title":"Novel Loss-of-Function Mutations in DNAH1 Displayed Different Phenotypic Spectrum in Humans and Mice","volume":"12","author":"Khan","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.semcdb.2014.01.003","article-title":"Microtubules and spermatogenesis","volume":"30","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_15","first-page":"119","article-title":"Regulation of microtubules in the seminiferous epithelium","volume":"1926","author":"Dunleavy","year":"2019","journal-title":"Microtubule Dyn. Methods Protoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1093\/humrep\/deaa348","article-title":"Andrological findings in infertile men with two (biallelic) CFTR mutations: Results of a multicentre study in Germany and Austria comprising 71 patients","volume":"36","author":"Messner","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.mce.2013.06.030","article-title":"KIF3A is essential for sperm tail formation and manchette function","volume":"377","author":"Lehti","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sweeney, H.L., and Holzbaur, E.L. (2018). Motor Proteins. Cold Spring Harb. Perspect. Biol., 10.","DOI":"10.1101\/cshperspect.a021931"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7004","DOI":"10.1073\/pnas.111145398","article-title":"All kinesin superfamily protein, KIF, genes in mouse and human","volume":"98","author":"Miki","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1002\/cm.20392","article-title":"Structures of kinesin motor proteins","volume":"66","author":"Marx","year":"2009","journal-title":"Cell Motil. Cytoskelet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.yexcr.2015.02.016","article-title":"Kinesin superfamily proteins (KIFs): Various functions and their relevance for important phenomena in life and diseases","volume":"334","author":"Hirokawa","year":"2015","journal-title":"Exp. Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nrm2774","article-title":"Kinesin superfamily motor proteins and intracellular transport","volume":"10","author":"Hirokawa","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1097-0169(1997)38:1<1::AID-CM1>3.0.CO;2-C","article-title":"The role of central apparatus components in flagellar motility and microtubule assembly","volume":"38","author":"Smith","year":"1997","journal-title":"Cell Motil. Cytoskelet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Morohoshi, A., Miyata, H., Shimada, K., Nozawa, K., Matsumura, T., Yanase, R., Shiba, K., Inaba, K., and Ikawa, M. (2020). Nexin-Dynein regulatory complex component DRC7 but not FBXL13 is required for sperm flagellum formation and male fertility in mice. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008585"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1038\/s41467-023-37868-0","article-title":"Native doublet microtubules from Tetrahymena thermophila reveal the importance of outer junction proteins","volume":"14","author":"Kubo","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Singharajkomron, N., Yodsurang, V., Seephan, S., Kungsukool, S., Petchjorm, S., Maneeganjanasing, N., Promboon, W., Dangwilailuck, W., and Pongrakhananon, V. (2022). Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314724"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3390\/genes2010260","article-title":"NEK1 Facilitates Cohesin Removal during Mammalian Spermatogenesis","volume":"2","author":"Holloway","year":"2011","journal-title":"Genes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e13277","DOI":"10.1111\/and.13277","article-title":"Comparison of sperm morphology and nuclear sperm quality in SPATA16- and DPY19L2-mutated globozoospermic patients","volume":"51","author":"Braham","year":"2019","journal-title":"Andrologia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/12729","article-title":"Globozoospermia in mice lacking the casein kinase II alpha\u2019 catalytic subunit","volume":"23","author":"Xu","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s10815-016-0715-3","article-title":"A new mutation identified in SPATA16 in two globozoospermic patients","volume":"33","author":"ElInati","year":"2016","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/humrep\/der377","article-title":"CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): A systemic review and meta-analysis","volume":"27","author":"Yu","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.21037\/tau.2020.04.05","article-title":"Genetics of CFTR and male infertility","volume":"10","author":"Bieniek","year":"2021","journal-title":"Transl. Androl. Urol."},{"key":"ref_33","first-page":"228","article-title":"CMTM2 is involved in spermiogenesis in mice","volume":"51","author":"Zhang","year":"2019","journal-title":"Beijing Da Xue Xue Bao Yi Xue Ban."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15363\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:50Z","timestamp":1760130590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,19]]},"references-count":33,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015363"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015363","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,19]]}}}