Abstract
BackgroundAsthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. DNAH9 is a core component of outer dynein arms in cilia and flagellum. It was reported that variants of DNAH9 (OMIM: 603330) might cause primary ciliary dyskinesia (PCD). However, variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported.MethodsWhole exome sequencing (WES) was performed for two individuals with nonsyndromic severe asthenozoospermia from two non-consanguineous families, and Sanger sequencing was performed to verify the identified variants and parental origins. Sperm routine analysis, sperm vitality rate and sperm morphology analysis were performed according the WHO guidelines 2010 (5th edition). Transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail. Quantitative realtime-PCR and immunofluorescence staining were performed to detect the expression of DNAH9-mRNA and location of DNAH9-protein. Furthermore, assisted reproductive procedures were applied.ResultsBy WES and Sanger sequencing, compound heterozygous DNAH9 (NM_001372.4) variants were identified in the two individuals with nonsyndromic severe asthenozoospermia (F1 II-1: c.302dupT, p.Leu101fs*47 / c.6956A > G, p.Asp2319Gly; F2 II-1: c.6294 T > A, p.Phe2098Leu / c.10571 T > A, p.Leu3524Gln). Progressive rates less than 1% with normal sperm morphology rates and normal vitality rates were found in both of the two subjects. No respiratory phenotypes, situs inversus or other malformations were found by detailed medical history, physical examination and lung CT scans etc. Moreover, the expression of DNAH9-mRNA was significantly decreased in sperm from F1 II-1. And expression of DNAH9 is lower in sperm tail by immunofluorescence staining in F1 II-1 compared with normal control. Notably, by intracytoplasmic sperm injection (ICSI), F1 II-1 and his partner successfully achieved clinical pregnancy.ConclusionsWe identified DNAH9 as a novel pathogenic gene for nonsyndromic severe asthenospermia, and ICSI can contribute to favorable pregnancy outcomes for these patients.
Highlights
Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood
Compound heterozygous variants in DNAH9 were identified in the individuals with severe asthenozoospermia To detect the cause of severe asthenozoospermia in these two patients, Whole exome sequencing (WES) analysis was performed
Pathogenic variants were obtained according to criteria as follows: allele frequencies < 1% in the ExAc_all, 1KGP and gnomAD databases; potentially high pathogenicity predicted by Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and Mutation Taster; extremely high expression in the testis
Summary
Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. Variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported. Infertility is worldwide problem, affecting 8–15% couples of childbearing age, and male factors might contribute to nearly half of the cases [1,2,3]. As one of the most common factors contributing to male infertility, asthenospermia might be associated with some cellular and molecular factors. Flagella/cilia, which is an important component of sperm tail structure, play a vital role in sperm motility system. Structural defects of flagella/cilia in sperm tail affect sperm motility directly. Ion channels, especially calcium channel is essential for sperm ion homeostasis, pH regulation and progressive motility. Lifestyle risk factors, such as smoking, alcohol consumption, chemical pesticides exposure, etc. [6]
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