Mutations in DNAH1, which Encodes an Inner Arm Heavy Chain Dynein, Lead to Male Infertility from Multiple Morphological Abnormalities of the Sperm Flagella
Open accessAbstract
Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum.
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Sperm tail defects were found to correlate with several genetic defects.
“Aside from the defect mentioned above, sperm tail defects were also found to correlate with several genetic defects.”
From Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review (2024) · cites this paper as [51]
Mutations on DNAH1, SPEF2, and SEPT12 were correlated with sperm tail anomalies.
“Several observational studies reported that mutations on DNAH1, SPEF2, and SEPT12 were correlated with sperm tail anomalies (51-53).”
From Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review (2024) · cites this paper as [51]
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Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human
Coutton, C., Vargas, A. S., Amiri-Yekta, A., Kherraf, Z.-E., Ben Mustapha, S. F., Le Tanno, P., Wambergue-Legrand, C., Karaouzène, T., Martinez, G., Crouzy, S., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02792-7 · Cited by 245 · see citing works
Self-citationFerreux, L., Bourdon, M., Chargui, A., Schmitt, A., Stouvenel, L., Lorès, P., Ray, P., Lousqui, J., Pocate-Cheriet, K., Santulli, P., et al. (2021) · Human Reproduction · doi:10.1093/humrep/deab200 · Cited by 44 · see citing works
Self-citationIsolated teratozoospermia: revisiting its relevance in male infertility: a narrative review
Atmoko, W., Savira, M., Shah, R., Chung, E., & Agarwal, A. (2024) · Translational Andrology and Urology · doi:10.21037/tau-23-397 · Cited by 23 · see citing works
“Several observational studies reported that mutations on DNAH1, SPEF2, and SEPT12 were correlated with sperm tail anomalies (51-53).”
Gatimel, N., Barbotin, A., Mery, L., Beauvillard, D., Bendayan, M., Boursier, A., Boueilh, T., Pereira, B., Chammas, J., Jacquet, J., et al. (2026) · Andrology · doi:10.1111/andr.70134 · Cited by 2 · see citing works
- Authors
- Ben Khelifa, M., Coutton, C., Zouari, R., Karaouzène, T., Rendu, J., Bidart, M., Yassine, S., Pierre, V., Delaroche, J., Hennebicq, S., Grunwald, D., Escalier, D., Pernet-Gallay, K., Jouk, P.-S., Thierry-Mieg, N., Touré, A., Arnoult, C., & Ray, P. F.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Ray, Pierre F.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 94
- Issue
- 1
- Pages
- 95-104
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3882734
- OpenAlex
- W1973632178
- Cited by
- 474
- References
- 1
- Citations by year
- 2026: 34 · 2025: 47 · 2024: 50 · 2023: 60 · 2022: 54 · 2021: 63 · 2020: 42 · 2019: 43 · 2018: 30 · 2017: 19 · 2016: 11 · 2015: 15 · 2014: 4
- FWCI
- 10.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (GENOPAT 2009, ANR-09-GENO-0013)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- DNAH1, male infertility, sperm flagella abnormalities, primary infertility, primary ciliary dyskinesia, North African populations
- MeSH terms
- Cilia, Flagella, Homozygote, Humans, Infertility, Male, Kartagener Syndrome, Male, Mutation, RNA, Messenger, Sperm Motility, Sperm Tail, Testis, Genetic Variation, Sequence Analysis, DNA, RNA Splice Sites, Axoneme, Axonemal Dyneins
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