Axonemal dynein gene dysfunction as a cause of male infertility: insights from DNAH family mutations.

Abstract

Male infertility is a complex disorder and defective sperm motility is one of the most common reasons for impaired fertility. The dynein axonemal heavy chain (DNAH) gene family encode molecular motors that form the structure of cilia and sperm flagella. Abnormalities in several DNAH genes have already been confirmed to be causative factors responsible for male infertility conditions, mainly including asthenozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF), and reproductive failure related to primary ciliary dyskinesia (PCD). Here, this review illustrates the current evidence regarding the involvement of members of the DNAH family in male infertility, along with summarizing their biological functions, genotypic and phenotypic correlations and clinical significance. Due to the breakthroughs of the technologies of whole-exome and whole-genome sequencing along with research with animal models and functional investigations, the diversity of reported causative DNAH mutations and their implications for the organization and function of sperm axonemes are currently better understood. DNAH1, DNAH8 and DNAH17 are the DNAH genes most frequently described as being involved in male infertility, though growing evidence also indicated that DNAH3, DNAH11, DNAH12 and DNAH14 also contribute to the male reproductive disorders. Implementation of testing DNAH genes into molecular diagnostics enhances the assessment of genes causing severe sperm motility disorders and aids genetic counseling of the affected families. Together with the genomic and functional data, further research will elucidate additional details for disease mechanisms and will bring benefit to more precise diagnosis and treatments of DNAH-associated male infertility.