Dataset Information

Novel bi-allelic mutations in DNAH1 cause multiple morphological abnormalities of the sperm flagella resulting in male infertility.

ABSTRACT:

Background

Male infertility is a major health concern and approximately 10-15% of cases are caused by genetic abnormalities. Defects in the sperm flagella are closely related to male infertility, since flagellar beating allows sperm to swim. The sperm of males afflicted with multiple morphological abnormalities of the flagella (MMAF) possess severe defects of the sperm flagella, may impair sperm motility and lead to male infertility. Currently, known genetic defects only account for MMAF in about 60% of patients and need more intensive efforts to explore the relationship between genes and MMAF.

Methods

The whole-exome sequencing (WES) was performed to analyze the genetic cause of the MMAF patient. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the morphology of sperm cells and to identify the ultrastructural characteristics of the flagella in the patient. The expression of DNAH1 was analyzed by sperm immunofluorescence staining.

Results

We identified the negative effects produced by the DNAH1 mutations c. 8170.C>T (p. R2724*) and c. 4670C>T (p. T1557M) on DNAH1 expression and the development of sperm flagella.

Conclusions

Our findings suggest that DNAH1 is associated with the formation of sperm flagella and homozygous loss-of-function mutations in DNAH1 can impair sperm motility and cause male infertility.

SUBMITTER: Jiang C

PROVIDER: S-EPMC8100829 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 DNAH2 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 DNAH2 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 in silico 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 DNAH2 variants underlying MMAF in general, we functionally characterized Dnah2-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 in Dnah2-null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis. Scanning and transmission electron microscopy analyses revealed that flagella ultrastructure is severely disorganized in Dnah2-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.