Biallelic loss-of-function variants of DNAH7 cause male infertility associated with asthenozoospermia in humans

Abstract

Although variants in DNAH family genes have been suggested as a main contributor to asthenozoospermia in humans, the role of DNAH7 on male fertility remains largely unexplored. In this study, loss-of-function variants in DNAH7 were identified in two unrelated infertile men with asthenozoospermia through whole exome sequencing, including compound heterozygous variants c.9702_9705del (p.Phe3234Leufs*52) and c.768G > A (p.Trp256*) in Patient 1, and compound heterozygous variants c.5650 C > T (p.Arg1884*) and c.768G > A (p. Trp 256*) in Patient 2. Interestingly, transmission electron microscopy results indicated a severe loss of inner dynein arms (IDAs) in the sperm flagella of both patients. Furthermore, immunofluorescent staining revealed a marked reduction of DNAH7 and other IDA-associated proteins, such as DNAH3 and DNAH6, in the patients' spermatozoa. In contrast, the expression of the outer dynein arms (ODA)-associated proteins, including DNAH8, DNAH11, DNAH17 and DNAI1, was comparable to that in normal controls. Moreover, the infertility of the patients harboring DNAH7 mutations could be successfully overcome by intracytoplasmic sperm injection treatment. Taken together, our findings confirmed that DNAH7 variants may contribute to asthenozoospermia by affecting flagellar IDA assembly, thereby enhancing our understanding of phenotype-genotype correlations in male infertility.