{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:30:01Z","timestamp":1791563401150,"version":"4.3.4"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,29]],"date-time":"2023-01-29T00:00:00Z","timestamp":1674950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM)","award":["FLAGELOME ANR-19-CE17-0014"],"award-info":[{"award-number":["FLAGELOME ANR-19-CE17-0014"]}]},{"name":"Centre National de la Recherche Scientifique (CNRS)","award":["FLAGELOME ANR-19-CE17-0014"],"award-info":[{"award-number":["FLAGELOME ANR-19-CE17-0014"]}]},{"name":"University Grenoble Alpes","award":["FLAGELOME ANR-19-CE17-0014"],"award-info":[{"award-number":["FLAGELOME ANR-19-CE17-0014"]}]},{"name":"French National Research Agency","award":["FLAGELOME ANR-19-CE17-0014"],"award-info":[{"award-number":["FLAGELOME ANR-19-CE17-0014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Male infertility is a common and complex disease and presents as a wide range of heterogeneous phenotypes. Multiple morphological abnormalities of the sperm flagellum (MMAF) phenotype is a peculiar condition of extreme morphological sperm defects characterized by a mosaic of sperm flagellum defects to a total asthenozoospermia. At this time, about 40 genes were associated with the MMAF phenotype. However, mutation prevalence for most genes remains individually low and about half of individuals remain without diagnosis, encouraging us to pursue the effort to identify new mutations and genes. In the present study, an a cohort of 167 MMAF patients was analyzed using whole-exome sequencing, and we identified three unrelated patients with new pathogenic mutations in DNHD1, a new gene recently associated with MMAF. Immunofluorescence experiments showed that DNHD1 was totally absent from sperm cells from DNHD1 patients, supporting the deleterious effect of the identified mutations. Transmission electron microscopy reveals severe flagellum abnormalities of sperm cells from one mutated patient, which appeared completely disorganized with the absence of the central pair and midpiece defects with a shortened and misshapen mitochondrial sheath. Immunostaining of IFT20 was not altered in mutated patients, suggesting that IFT may be not affected by DNHD1 mutations. Our data confirmed the importance of DNHD1 for the function and structural integrity of the sperm flagellum. Overall, this study definitively consolidated its involvement in MMAF phenotype on a second independent cohort and enriched the mutational spectrum of the DNHD1 gene.<\/jats:p>","DOI":"10.3390\/ijms24032559","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:58:25Z","timestamp":1675054705000},"page":"2559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["New Mutations in DNHD1 Cause Multiple Morphological Abnormalities of the Sperm Flagella"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-9096","authenticated-orcid":false,"given":"Guillaume","family":"Martinez","sequence":"first","affiliation":[{"name":"CHU Grenoble Alpes, UM de G\u00e9n\u00e9tique Chromosomique, 38000 Grenoble, France"},{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"Barbotin","sequence":"additional","affiliation":[{"name":"CHU Lille, Institut de Biologie de la Reproduction-Spermiologie-CECOS, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8962-3447","authenticated-orcid":false,"given":"Caroline","family":"Cazin","sequence":"additional","affiliation":[{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"},{"name":"CHU de Grenoble, UM GI-DPI, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeina","family":"Wehbe","sequence":"additional","affiliation":[{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e8le","family":"Boursier","sequence":"additional","affiliation":[{"name":"CHU Lille, Institut de Biologie de la Reproduction-Spermiologie-CECOS, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8099-7984","authenticated-orcid":false,"given":"Amir","family":"Amiri-Yekta","sequence":"additional","affiliation":[{"name":"Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran 16635-148, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas","family":"Daneshipour","sequence":"additional","affiliation":[{"name":"Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran 16635-148, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyedeh-Hanieh","family":"Hosseini","sequence":"additional","affiliation":[{"name":"Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran 16635-148, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Rives","sequence":"additional","affiliation":[{"name":"Team Adrenal and Gonadal Pathophysiology, Inserm, U1239 NorDIC, University Rouen Normandie, 76000 Rouen, France"},{"name":"Reproductive Biology Laboratory\u2014CECOS, Rouen University Hospital, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Feraille","sequence":"additional","affiliation":[{"name":"Team Adrenal and Gonadal Pathophysiology, Inserm, U1239 NorDIC, University Rouen Normandie, 76000 Rouen, France"},{"name":"Reproductive Biology Laboratory\u2014CECOS, Rouen University Hospital, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-2853","authenticated-orcid":false,"given":"Nicolas","family":"Thierry-Mieg","sequence":"additional","affiliation":[{"name":"TIMC, University Grenoble Alpes, CNRS, UMR 5525, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Bidart","sequence":"additional","affiliation":[{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"},{"name":"CHU Grenoble Alpes, Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire: Maladies H\u00e9r\u00e9ditaires et Oncologie, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Satre","sequence":"additional","affiliation":[{"name":"CHU Grenoble Alpes, UM de G\u00e9n\u00e9tique Chromosomique, 38000 Grenoble, France"},{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Arnoult","sequence":"additional","affiliation":[{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre F.","family":"Ray","sequence":"additional","affiliation":[{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"},{"name":"CHU de Grenoble, UM GI-DPI, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0351-6689","authenticated-orcid":false,"given":"Zine-Eddine","family":"Kherraf","sequence":"additional","affiliation":[{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"},{"name":"CHU de Grenoble, UM GI-DPI, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-8098","authenticated-orcid":false,"given":"Charles","family":"Coutton","sequence":"additional","affiliation":[{"name":"CHU Grenoble Alpes, UM de G\u00e9n\u00e9tique Chromosomique, 38000 Grenoble, France"},{"name":"Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1093\/humupd\/dmx022","article-title":"Temporal Trends in Sperm Count: A Systematic Review and Meta-Regression Analysis","volume":"23","author":"Levine","year":"2017","journal-title":"Hum. 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Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ajhg.2018.12.013","article-title":"Bi-Allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice","volume":"104","author":"Coutton","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/s41467-017-02792-7","article-title":"Mutations in CFAP43 and CFAP44 Cause Male Infertility and Flagellum Defects in Trypanosoma and Human","volume":"9","author":"Coutton","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","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. 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