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

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.

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.

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.

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.