CFAP300 loss-of-function variant causes primary ciliary dyskinesia and male infertility via disrupting sperm flagellar assembly and acrosome formation.

Hua-Yan YIN; Yu-Qi ZHOU; Qun-Shan SHEN; Zi-Wen CHEN; Jie-Ru LI; Huan WU; Yun-Xia CAO; Rui GUO; Bing SONG

Return

CFAP300 loss-of-function variant causes primary ciliary dyskinesia and male infertility via disrupting sperm flagellar assembly and acrosome formation.

Author: Hua-Yan YIN ¹ ; Yu-Qi ZHOU ¹ ; Qun-Shan SHEN ¹ ; Zi-Wen CHEN ² ; Jie-Ru LI ³ ; Huan WU ¹ ; Yun-Xia CAO ¹ ; Rui GUO ¹ ; Bing SONG ¹
Author Information

1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
2. The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
3. The Second School of Clinical Medicine, Anhui Medical University, Hefei 230032, China.
Publication Type:Case Reports
Keywords: asthenoteratozoospermia; male infertility; primary ciliary dyskinesia
MeSH: Humans; Male; Infertility, Male/pathology*; Acrosome/pathology*; Sperm Tail/pathology*; Pedigree; Spermatozoa; Adult; Loss of Function Mutation; Ciliary Motility Disorders/genetics*; Spermatogenesis/genetics*; Female
From: Asian Journal of Andrology 2025;27(6):743-750
CountryChina
Language:English
Abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired motility of cilia and flagella. Mutations in cilia- and flagella-associated protein 300 ( CFAP300 ) are associated with human PCD and male infertility; however, the underlying pathogenic mechanisms remain poorly understood. In a consanguineous Chinese family, we identified a homozygous CFAP300 loss-of-function variant (c.304delC) in a proband presenting with classical PCD symptoms and severe sperm abnormalities, including dynein arm deficiency and acrosomal malformation, as confirmed by transmission electron microscopy (TEM). Histological analysis revealed multiple morphological abnormalities of the sperm flagella in CFAP300 -mutant individual, whereas immunofluorescence demonstrated markedly reduced CFAP300 expression in the spermatozoa of the proband. Furthermore, tandem mass tag (TMT)-based quantitative proteomics showed that the CFAP300 mutation reduced key spermatogenesis proteins (e.g., sperm flagellar 2 [SPEF2], solute carrier family 25 member 31 [SLC25A31], and A-kinase anchoring protein 3 [AKAP3]) and mitochondrial ATP synthesis factors (e.g., SLC25A31, cation channel sperm-associated 3 [CATSPER3]). It also triggered abnormal increases in autophagy-related proteins and signaling mediator phosphorylation. These molecular alterations are likely to contribute to progressive deterioration of sperm ultrastructure and function. Notably, successful pregnancy was achieved via intracytoplasmic sperm injection (ICSI) using the proband's sperm. Overall, this study expands the known CFAP300 mutational spectrum and offers novel mechanistic insights into its role in spermatogenesis.