A homozygous splicing mutation in CCDC39 caused multiple morphological abnormalities of the flagella in an infertile man with primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a severe sperm defect, leading to male infertility. PCD affects both respiratory function and sperm motility, as motile cilia and sperm flagella rely on axonemal architecture. Multiple morphological abnormalities of the sperm flagella (MMAF) is a distinct form of asthenoteratozoospermia, characterized by a heterogeneous spectrum of flagellar defects. In recent years, coiled-coil domain-containing (CCDC) genes have been shown to play crucial roles in both MMAF and PCD. In this study, a homozygous mutation in CCDC39, c.1528-2A>G, was identified in a patient of a consanguineous Chinese family presenting a typical PCD phenotype. Quantitative real-time polymerase chain reaction (qPCR) and immunofluorescence demonstrated a significant reduction in CCDC39 mRNA levels and loss of the expression of CCDC39 and other axoneme dynein proteins, respectively. Diff-Quik staining and semen analysis from the patient revealed severely reduced sperm motility, in addition to a pronounced MMAF phenotype. Severe axonemal disorganization and ultrastructural defects were consistent with the PCD phenotype in the patient, further suggesting that CCDC39 deficiency is linked to both infertility and systemic ciliary dysfunction. After intracytoplasmic sperm injection (ICSI) treatment, the CCDC39-deficient patient achieved a successful pregnancy. Overall, our findings clearly indicate that the c.1528-2A>G mutation in CCDC39 is associated with the pathogenesis of both MMAF and PCD, thereby advancing genetic diagnosis, treatment, and prognosis related to in vitro fertilization (IVF) outcomes associated with the MMAF phenotype in PCD patients.