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

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 m...

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Bibliographic Details
Published in:	Frontiers in cell and developmental biology 2021-04, Vol.9, p.662903
Main Authors:	Hwang, Jae Yeon, Nawaz, Shoaib, Choi, Jungmin, Wang, Huafeng, Hussain, Shabir, Nawaz, Mehboob, Lopez-Giraldez, Francesc, Jeong, Kyungjo, Dong, Weilai, Oh, Jong-Nam, Bilguvar, Kaya, Mane, Shrikant, Lee, Chang-Kyu, Bystroff, Christopher, Lifton, Richard P, Ahmad, Wasim, Chung, Jean-Ju
Format:	Article
Language:	eng
Subjects:	asthenozoospermia Cell and Developmental Biology DNAH2 male infertility MMAF sperm flagellum WES
Online Access:	Get full text
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Summary:	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 the gene 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) in by 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, and analysis models reveal that the non-synonymous variant substitutes a residue in dynein heavy chain domain and destabilizes DNAH2. To better understand the pathogenicity of various variants underlying MMAF in general, we functionally characterized -mutant mice generated by CRISPR/Cas9 genome editing. -null males, but not females, are infertile. -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 in -null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis. Scanning and transmission electron microscopy analyses revealed that flagella ultrastructure is severely disorganized in -null sperm. Absence of DNAH2 compromises the expression of other axonemal components such as DNAH1 and RSPH3. Our results demonstrate that DNAH2 is essential for multiple steps in sperm flagella formation and provide insights into molecular and cellular mechanisms of MMAF pathogenesis.
ISSN:	2296-634X 2296-634X