A Biallelic Mutation in CCDC103 Impairs Sperm Motility due to the Absence of Dynein Arms

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by destructive respiratory disease and laterality abnormalities due to randomized left–right body asymmetry. In men, PCD is also often associated with infertility due to immotile sperm owing to a malfunction of the sperm flagella. Pathogenic mutations have been found in more than 50 genes. Nonetheless, not all patients with PCD experience infertility. Therefore, to better understand the impact of PCD-associated mutations on male fertility, it is necessary to clarify the role of these genes in spermatogenesis. The CCDC103 p.His154Pro mutation has a high prevalence in PCD. Here, we present the identification and functional analysis of a biallelic mutation in CCDC103 identified in a familial case of PCD associated with male infertility. The biallelic CCDC103 mutations, NM_213607:c.161_162del(p.His55Serfs ∗9) and NM_213607:c.461A > C (p.His154Pro), were identified by whole-exome sequencing. Sanger sequencing validation was performed on all available family members, and the mutation was recessively separated with an infertility phenotype. The c.161_162del mutation breaks the reading frame of the protein and, therefore, is predicted to produce a nonfunctional protein. The tertiary structure of CCDC103-mutated protein indicated a significant conformational change that likely affected protein function. Transmission electron microscopy of spermatozoa showed that both the mid and principal regions of the flagellum lacked dynein arms, which was confirmed via immunofluorescence staining. Using the method of laser-assisted immotile sperm selection combined with intracytoplasmic sperm injection, the patient’s wife has a successful clinical pregnancy. These results extend the phenotype spectrum of the CCDC103 mutation in PCD.