IQ motif family genes in male infertility: pathogenesis, mechanisms, and clinical perspectives

This review examines the critical role of IQ motif family genes in male infertility. Characterized by conserved calmodulin-binding IQ domains, these genes, including IQUB, IQCN, and IQCH, exhibit reproductive tissue-specific expression and regulate fundamental processes in spermatogenesis and sperm function, such as Ca²⁺ signaling, cytoskeletal dynamics, and RNA splicing. Specific loss-of-function mutations are strongly linked to distinct clinical phenotypes: IQUB variants to asthenozoospermia, IQCN mutations to total fertilization failure, and IQCH deficiency to azoospermia. The article discusses emerging diagnostic applications, including genetic screening via whole-exome sequencing and the evaluation of sperm protein biomarkers like IQCD. Furthermore, it outlines mechanism-informed therapeutic strategies, from clinically applied artificial oocyte activation for IQCN defects to preclinical explorations of gene correction. The synthesis underscores how research on this gene family is advancing the field toward precision medicine in male infertility.