Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 107, Issue 2, Pages 330-341Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.06.004
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) (KAKENHI) [JP17H04987, JP19H05750]
- National Natural Science Foundation of China [31625015, 31521003, 81901541, 81971441, 81871200]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01HD087157, R01HD088412]
- Bill and Melinda Gates Foundation [INV-001902]
- Institut National de la Santeet de la Recherche Medicale (Inserm)
- Centre National de la Recherche Scientifique (CNRS)
- Universite de Paris
- Shanghai Medical Center of Key Programs for Female Reproductive Diseases [2017ZZ01016]
- Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
- French National Research Agency (MASFLAGELLA) [ANR-14-CE15-0002]
- French National Research Agency (FLAGEL-OME) [ANR18-CE17-0014]
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Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men. Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants, variants which were either absent or rare in the control human population and were predicted to be deleterious by multiple bioinformatic tools. Re-analysis of exome data from a second cohort of 167 MMAF-affected men from France, Iran, and North Africa permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant. DNAH8 encodes a dynein axonemal heavy-chain component that is expressed preferentially in the testis. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella. Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17. Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility. Interestingly, intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes. Collectively, our experimental observations from humans and mice demonstrate that DNAH8 is essential for sperm flagellar formation and that bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF.
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