Novel variants in DNAH17 cause sperm flagellar outer dynein arm defects but not total fertilization failure after ICSI.

RESEARCH QUESTION: Are there novel variants in the dynein axonemal heavy chain 17 (DNAH17) gene related to male infertility? What is the relationship between total fertilization failure (TFF) and DNAH17 deficiency?

DESIGN

Whole-exome sequencing and Sanger sequencing were performed in a cohort of 75 Chinese patients with multiple morphological abnormalities of sperm flagella (MMAF) to identify potential novel gene variants. Papanicolaou staining and electron microscopy were employed to observe sperm morphology and ultrastructure. Proteomic analysis and comprehensive functional analysis were performed to elucidate the relationship between DNAH17 deficiency and TFF at the molecular level.

RESULTS

Ten novel variants in DNAH17 were identified in five unrelated families with five infertile male probands. These variants exhibited an autosomal-recessive inheritance pattern and caused deficiency of DNAH17 in spermatozoa. Typical MMAF characteristics and deformations in the flagellar ultrastructure of DNAH17-deficient spermatozoa were observed. Comprehensive functional analysis revealed that DNAH17 deficiency impaired the assembly and docking of outer dynein arms, affected the acrosome reaction, and disrupted mitochondrial function. Fertilization-related proteins, such as actin-like protein 7A and PRKCA-binding protein, were normal, while reduced yet ≥30% concentrations of phospholipase C zeta were detected, implying an indirect relationship between DNAH17 deficiency and TFF. Four of the affected couples obtained transferable embryos following intracytoplasmic sperm injection without artificial oocyte activation.

CONCLUSIONS

These findings broaden the variant spectrum of DNAH17, and illuminate the complex molecular basis of male infertility associated with DNAH17 deficiency, particularly its heterogeneous impact on fertilization. The study provided vital insights for genetic diagnosis and counselling in males affected by MMAF.