Xiangrong Tang: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Shunhua Long: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Fei Xie: Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China.
Jing Ma: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Guicen Liu: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Haiyuan Liao: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Tingwenyi Hu: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Haibing Yu: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Ling Liu: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China.
Guoning Huang: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China. Electronic address: gnhuang217@sina.com.
Tingting Lin: Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Centre for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Clinical Research Centre for Reproductive Medicine, Chongqing Health Centre for Women and Children, Chongqing, China. Electronic address: yuting9263@163.com.
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.
