A novel homozygous LRRC6 mutation causes male infertility with asthenozoospermia and primary ciliary dyskinesia in humans

作者：Shengjia Shi, Xiangrong Tang, Shunhua Long, Jie Yang, Tianwei Wang, Hongmei Wang, Tingwenyi Hu, Juanzi Shi, Guoning Huang, Sen Qiao, Tingting Lin · 发表于：Andrology · 年份：2024 · DOI：10.1111/andr.13685 · 被引用次数：7 · 研究领域：Cystic Fibrosis Research Advances、Genetic and Kidney Cyst Diseases、Sperm and Testicular Function

BACKGROUND: Dysfunction of motile cilia, including respiratory cilia and sperm flagella, typically leads to primary ciliary dyskinesia and male infertility or low fertility in humans. Genetic defects of LRRC6 have been associated with primary ciliary dyskinesia and asthenozoospermia due to abnormal ultrastructure of ciliated axonemes. OBJECTIVES: To identify novel mutations of the LRRC6 gene related to multiple morphological abnormalities of the sperm flagella and male infertility and investigate the underlying molecular mechanisms involved. MATERIALS AND METHODS: The LRRC6 mutations were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning, and transmission electron microscopy were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Further tandem mass tagging proteomics analyses were performed to explore the effect of mutations and confirmed by immunostaining and western blotting. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic LRRC6 mutations. RESULTS: In this study, we identified a novel homozygous LRRC6 mutation in a consanguineous family, characterized by asthenozoospermia and primary ciliary dyskinesia. Further Semen parameter and morphology analysis demonstrate that the novel LRRC6 mutation leads to a significant reduction in sperm flagella length, a decrease in sperm progressive motility parameters, and abnor...