{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:52:06Z","timestamp":1792806726090,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T00:00:00Z","timestamp":1693180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008982","name":"Qatar National Research Fund","doi-asserted-by":"publisher","award":["NPRP12S\u20100318\u2010190394"],"award-info":[{"award-number":["NPRP12S\u20100318\u2010190394"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Although defects in sperm morphology and physiology lead to male infertility, in many instances, the exact disruption of molecular pathways in a given patient is often unknown. The glycolytic pathway is an essential process to supply energy in sperm cell motility. Enolase 4 (<jats:italic>ENO4)<\/jats:italic> is crucial for the glycolytic process, which provides the energy for sperm cells in motility. <jats:italic>ENO4<\/jats:italic> is located in the sperm principal piece and is essential for the motility and organization of the sperm flagellum. In the present study, we characterized a family with asthenozoospermia and abnormal sperm morphology as a result of a variant in the enolase 4 (<jats:italic>ENO4<\/jats:italic>) gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Computer\u2010assisted semen analysis, papanicolaou smear staining and scanning electron microscopy were used to examine sperm motility and morphology for semen analysis in patients. For genetic analysis, whole\u2010exome sequencing followed by Sanger sequencing was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two brothers in a consanguineous family were being clinically investigated for sperm motility and morphology issues. Genetic analysis by whole\u2010exome sequencing revealed a homozygous variant [c.293A&gt;G, p.(Lys98Arg)] in the <jats:italic>ENO4<\/jats:italic> gene that segregated with infertility in the family, shared by affected but not controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In view of the association of asthenozoospermia and abnormal sperm morphology in <jats:italic>Eno4<\/jats:italic> knockout mice, we consider this to be the first report describing the involvement of <jats:italic>ENO4<\/jats:italic> gene in human male infertility. We also explore the possible involvement of another variant in explaining other phenotypic features in this family.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3583","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T01:00:04Z","timestamp":1693270804000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A variant in sperm\u2010specific glycolytic enzyme enolase 4 (<i>ENO4<\/i>) causes human male infertility"],"prefix":"10.1002","volume":"26","author":[{"given":"Shoaib","family":"Nawaz","sequence":"first","affiliation":[{"name":"Department of Human Genetics\u2010Precision Medicine Program Sidra Medicine  Doha Qatar"},{"name":"Department of Biotechnology, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shabir","family":"Hussain","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad  Islamabad Pakistan"},{"name":"Clinical And Molecular Metabolism Research (CAMM) Program, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Bilal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad  Islamabad Pakistan"},{"name":"Department of Pathology and Laboratory Medicine Agha Khan University  Karachi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najeeb","family":"Syed","sequence":"additional","affiliation":[{"name":"Department of Human Genetics\u2010Precision Medicine Program Sidra Medicine  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khurram","family":"Liaqat","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad  Islamabad Pakistan"},{"name":"Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology Columbia University Medical Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammira Al\u2010Shabeeb","family":"Akil","sequence":"additional","affiliation":[{"name":"Department of Human Genetics\u2010Precision Medicine Program Sidra Medicine  Doha Qatar"},{"name":"Precision Medicine in Diabetes Prevention Lab, Population Genetics Sidra Medicine  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid A.","family":"Fakhro","sequence":"additional","affiliation":[{"name":"Department of Human Genetics\u2010Precision Medicine Program Sidra Medicine  Doha Qatar"},{"name":"Department of Genetic Medicine Weill Cornell Medical College  Doha Qatar"},{"name":"College of Health and Life Sciences Hamad Bin Khalifa University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1541-7258","authenticated-orcid":false,"given":"Wasim","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University Islamabad  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102458\u201011\u2010760"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.f.1895"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gar050"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12857"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.07.014"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy034"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2340\u20109320(15)30004\u20109"},{"key":"e_1_2_10_9_1","unstructured":"Pe\u00f1a VegaFJ Ortiz Rodr\u00edguezJM Gaitskell PhillipsG Gil AnayaMC Ortega FerrusolaC Mart\u00edn CanoFE.An integrated overview on the regulation of sperm metabolism (glycolysis\u2010Krebs cycle\u2010oxidative phosphorylation)."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/biochem2030014"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2019.9926"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.112.107128"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407708101"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2018.04.022"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gau080"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109025"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202200805RR"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706974200"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0071213"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.21.7481\u20107494.2001"},{"key":"e_1_2_10_21_1","unstructured":"WHO.Examination and processing of human semen vol.V Pressed. 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