Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice

作者：Jae Yeon Hwang, Shoaib Nawaz, Jungmin Choi, Huafeng Wang, Shabir Hussain, Mehboob Nawaz, Francesc López‐Giráldez, Kyungjo Jeong, Weilai Dong, Jong‐Nam Oh, Kaya Bilgüvar, Shrikant Mane, Chang-Kyu Lee, Christopher Bystroff, Richard P. Lifton, Wasim Ahmad, Jean‐Ju Chung · 发表于：Frontiers in Cell and Developmental Biology · 年份：2021 · DOI：10.3389/fcell.2021.662903 · 被引用次数：80 · 研究领域：Sperm and Testicular Function、Reproductive Biology and Fertility、Ovarian function and disorders

Asthenozoospermia accounts for over 80% of primary male infertility cases. Reduced sperm motility in asthenozoospermic patients are often accompanied by teratozoospermia, or defective sperm morphology, with varying severity. Multiple morphological abnormalities of the flagella (MMAF) is one of the most severe forms of asthenoteratozoospermia, characterized by heterogeneous flagellar abnormalities. Among various genetic factors known to cause MMAF, multiple variants in theDNAH2gene are reported to underlie MMAF in humans. However, the pathogenicity by DNAH2 mutations remains largely unknown. In this study, we identified a novel recessive variant (NM_020877:c.12720G > T;p.W4240C) inDNAH2by whole-exome sequencing, which fully co-segregated with the infertile male members in a consanguineous Pakistani family diagnosed with asthenozoospermia. 80–90% of the sperm from the patients are morphologically abnormal, andin silicoanalysis models reveal that the non-synonymous variant substitutes a residue in dynein heavy chain domain and destabilizes DNAH2. To better understand the pathogenicity of variousDNAH2variants underlying MMAF in general, we functionally characterizedDnah2-mutant mice generated by CRISPR/Cas9 genome editing.Dnah2-null males, but not females, are infertile.Dnah2-null sperm cells display absent, short, bent, coiled, and/or irregular flagella consistent with the MMAF phenotype. We found misexpression of centriolar proteins and delocalization of annulus proteins inDnah...