Discovery of a molecule that is essential for the formation of sperm flagella (Ikawa Lab, in AJHG)

Groups including Department of Experimental Genome Research discovered a molecule that is essential for the formation of sperm flagella. This is an international collaborative work with Fudan University, Nanjing Medical University, Anhui Medical University, Xiamen University, Institut Cochin, Centre National de la Recherche Scientifique, Université de Paris, Assistance publique – Hôpitaux de Paris, Grenoble Alpes University, Centre Hospitalier Universitaire Grenoble Alpes, and Eurofins Biomnis.

About 1 in 6 couples suffer from infertility, with male factors contributing to half of the cases. One cause of male infertility is impaired formation of sperm flagella (MMAF, Multiple Morphological Abnormalities of the Sperm Flagella) (Figure 1); however, its etiology is still unclear. In this study, we performed whole exome sequencing in a cohort of 257 MMAF-affected men and found DNAH8 variations in 3 men. DNAH8 is evolutionary conserved from unicellular organism to mammals and is a component of dynein that is important for flagellar motility. Our results indicate that DNAH8 is essential for not only flagellar motility but also flagellar formation.

We also generated Dnah8 knockout (KO) mice, which were male infertile because of abnormal flagellar formation (Figure 2). We performed IntraCytoplasmic Sperm Injection (ICSI) and found that normal pups could be obtained from Dnah8 KO sperm. ICSI was also successful and resulted in a live birth in humans, indicating that ICSI could be a promising treatment for infertile men harboring bi-allelic DNAH8 variants.

This article was published in the American Journal of Human Genetics online.

Title: Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility

Authors: Chunyu Liu#, Haruhiko Miyata#, Yang Gao#, Yanwei Sha#, Shuyan Tang#, Zoulan Xu#, Marjorie Whitfield, Catherine Patrat, Huan Wu, Emmanuel Dulioust, Shixiong Tian, Keisuke Shimada, Jiangshan Cong, Taichi Noda, Hang Li, Akane Morohoshi, Caroline Cazin, Zine-Eddine Kherraf, Christophe Arnoult, Li Jin, Xiaojin He, Pierre F. Ray†, Yunxia Cao†, Aminata Touré†, Feng Zhang†*, and Masahito Ikawa†*. (#:equal contribution, †: equal contribution, *: equal correspondence)