Broadening the ARMC2 mutational phenotype: linking multiple morphological abnormalities of the Flagella to Pulmonary Manifestations in Primary Ciliary Dyskinesia

• DOI: 10.1186/s12958-025-01385-0
• Publication Date: 2025-03-29T18:22:46Z
• Authors: Baoyan Wu; Wenhao Zhang; Hui Yu; Lewen Ruan; Kai Wang; Meng Gu; Hao Geng; Jiajun Fang; Chuan Xu; Yuying Sheng; Qing Tan; Qunshan Shen; Zongliu Duan; Huan Wu; Rong Hua; Rui Guo; Zhaolian Wei; Ping Zhou; Yuping Xu; Yunxia Cao; Xiaojin He; Kuokuo Li; Mingrong Lv; Dongdong Tang

Severe asthenoteratozoospermia, a prevalent cause of male infertility, has increasingly been associated with ARMC2 variants that Multiple Morphological Abnormalities the Sperm Flagella (MMAF). Although is also expressed in other ciliary structures, no studies have yet reported link between gene and symptoms Primary Ciliary Dyskinesia (PCD). Here, we performed whole-exome sequencing (WES) on Chinese subjects MMAF to identify potential genetic variants. Sanger was used validate candidate morphology assessed using modified hematoxylin eosin (H&E) staining, transmission electron microscopy (TEM) observe ultrastructural defects sperm flagella. Western blot analysis immunofluorescence (IF) spermatozoa were evaluate variations structural protein. Additionally, intracytoplasmic injection (ICSI) applied for assisted fertilization. We identified two compound heterozygous one homozygous variant (P1: c.1030_1042del, p.T344fs/c.1331G > A, p.R444H; P2:c.1264C T, p.R422X) unrelated individuals. Notably, addition MMAF, individual P2 exhibited classic PCD lungs, including recurrent airway infections, bronchitis, rhinosinusitis. analyses obtained from individuals revealed dramatic disorganization axonemal peri-axonemal as well absence central pair complex (CPC). Immunoblotting assays reduced expression abnormality various axonal proteins. Further reproduction outcomes showed conceived successfully after Intracytoplasmic Injection (ICSI). Overall, this study significantly expanded mutational phenotype ARMC2, marking first discovery PCD-related pulmonary phenotypes outside reproductive system. This work establishes association typical lays groundwork further investigation into molecular mechanisms both flagellogenesis ciliogenesis.