ODAD1 – Primary Ciliary Dyskinesia 20

ODAD1 encodes the outer dynein arm docking complex subunit 1, essential for attachment of outer dynein arms (ODAs) to motile cilia. Biallelic ODAD1 mutations underlie ciliary dyskinesia, primary, 20 (CILD20), a subtype of primary ciliary dyskinesia (PCD) characterized by defective ODA assembly and variable situs abnormalities ([PMID:32855706]).

Inheritance is autosomal recessive with three unrelated probands reported. A Han-Chinese patient with situs inversus totalis harbored a homozygous missense variant c.584T>C (p.Leu195Pro) ([PMID:32855706]). A second individual presented with an unusually mild PCD phenotype and a homozygous noncanonical splice-site mutation c.1502+5G>A, resulting in truncated protein expression ([PMID:35163670]). A third patient carried compound heterozygous splice-site mutations c.71-2A>C and c.598-2A>C, leading to aberrant transcripts and loss of wild-type ODAD1 ([PMID:38028630]).

Segregation data are limited, but all variants fit an autosomal recessive pattern. In total, 3 probands and 4 pathogenic alleles (1 missense, 3 splice-site) have been documented, with no recurrent or population-specific founder variants described.

Functional studies in patient-derived nasal epithelial cells demonstrate that the c.1502+5G>A allele produces a truncated ODAD1 that still localizes to the axoneme, allowing partial ODA assembly and residual ciliary motility ([PMID:35163670]). Splice-site mutations cause complete loss of wild-type ODAD1, outer dynein arm defects, and reduced ciliary beat frequency, while truncated proteins retain partial function and disrupt ODAD1–ODAD3 interactions, consistent with a hypomorphic loss-of-function mechanism ([PMID:38028630]).

No studies to date contradict ODAD1’s role in CILD20. Additional large-scale cohort and segregation studies would strengthen the evidence. Key take-home: Biallelic ODAD1 variants cause Primary Ciliary Dyskinesia 20, and functional assays of ODA docking inform variant interpretation and therapeutic development.

References

• Experimental and therapeutic medicine • 2020 • Identification of a CCDC114 variant in a Han-Chinese patient with situs inversus. PMID:32855706
• International journal of molecular sciences • 2022 • Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype. PMID:35163670
• Frontiers in genetics • 2023 • ODAD1 variants resulting from splice-site mutations retain partial function and cause primary ciliary dyskinesia with outer dynein arm defects. PMID:38028630

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