IQUB mutation induces radial spoke 1 deficiency causing asthenozoospermia with normal sperm morphology in humans and mice

作者：Tingwenyi Hu, Xiangrong Tang, Tiechao Ruan, Shunhua Long, Guicen Liu, Jing Ma, Xueqi Li, Ruoxuan Zhang, Guoning Huang, Ying Shen, Tingting Lin · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02043-z · 被引用次数：11 · 研究领域：Sperm and Testicular Function、Developmental Biology and Gene Regulation、Wnt/β-catenin signaling in development and cancer

Asthenozoospermia (ASZ) accounts for about 20-40% of male infertility, and genetic factors, contributing to 30-40% of the causes of ASZ, still need further exploration. Radial spokes (RSs), a T-shaped macromolecular complex, connect the peripheral doublet microtubules (DMTs) to a central pair (CP), forming a CP-RS-DMT structure to regulate the beat frequency and amplitude of sperm flagella. To date, many components of RSs and their functions in human sperm flagella remain unclear. We recruited a cohort of 323 infertile males with ASZ between August 2019 and June 2024. Genetic mutations were identified by whole-exome sequencing. Computer-aided sperm analysis, Papanicolaou staining, and electron microscopy were applied to evaluate the motility, morphology, and ultrastructure of spermatozoa, respectively. Protein mass spectrometry, western blotting, and bioinformatic analyses were performed to identify critical components of mammalian RS1 to model its structure and explore the pathological mechanism of IQUB deficiency. Intracytoplasmic sperm injection (ICSI) was applied for the patient and Iqub −/− mice. We identified a novel homozygous IQUB mutation [c.842del (p.L281Pfs*28)] in an ASZ male with normal sperm morphology (ANM), which resulted in the complete loss of IQUB in sperm flagella. Deficiency of RS1, but not RS2 or RS3, was observed in both IQUB 842del patient and Iqub −/− mice, and resulted in the reduction of sperm kinetic parameters, indicating the critical role of IQUB...