{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent evidence has established that CCDC39 is a critical structural component of motile cilia, localizing to the axoneme where it is indispensable for the assembly of inner dynein arms and the dynein regulatory complex. This protein plays an essential role in organizing the distinct 96‐nm repeat units required for precise coordination of ciliary beating, and its loss-of-function is associated with a stiff, rapid, and aberrant ciliary motility pattern that underlies primary ciliary dyskinesia (PCD). Mutations in CCDC39 therefore disrupt normal ciliary assembly and function, leading to the chronic respiratory infections, laterality defects, and male infertility observed in affected individuals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n\nDissection of the genetic landscape in PCD has revealed that null mutations in CCDC39, along with mutations in its functional partner CCDC40, are frequent in cases characterized by axonemal disorganization and loss of inner dynein arms. In several studies, including those leveraging positional cloning in animal models and targeted next-generation sequencing in human cohorts from diverse populations, biallelic mutations—often homozygous and predicted to truncate the protein—have been identified. These mutations are associated with a characteristic ultrastructural phenotype where, despite largely preserved radial spoke architecture, the integrity of the inner dynein arm and the molecular ruler complex is compromised."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n\nFurthermore, the clinical spectrum associated with CCDC39 mutations extends into domains such as male infertility, where defects in ciliary/flagellar motility manifest as asthenozoospermia and multiple morphological abnormalities of sperm flagella (MMAF). Quantitative analyses of ciliary beating in such patients underscore the fundamental role of CCDC39 in maintaining effective ciliary dynamics—a finding that complements broader genotype-phenotype correlations in PCD."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anne-Christine Merveille, Erica E Davis, Anita Becker-Heck, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Crit Care Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1164/rccm.201409-1672OC"}], "href": "https://doi.org/10.1164/rccm.201409-1672OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25493340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25493340"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Dinu Antony, Anita Becker-Heck, Maimoona A Zariwala, et al. 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