CCDC151 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD; MONDO:0016575) is an autosomal recessive disorder of motile cilia characterized by chronic sinusitis, bronchiectasis, situs inversus, and infertility. The coiled-coil domain containing 151 gene (CCDC151, HGNC:28303 Gene Symbol) encodes a protein essential for axonemal dynein arm assembly and docking in motile cilia. Loss-of-function variants in CCDC151 have been identified as causative for PCD across multiple ethnicities under an autosomal recessive inheritance model.

Genetic evidence includes four unrelated probands with biallelic truncating variants: c.925G>T (p.Glu309Ter) ([PMID:25224326]), c.167delG (p.Gly56AspfsTer26) ([PMID:32490514]), c.325G>T (p.Glu109Ter) ([PMID:30504913]), and c.1166_1169dupAGAC (p.Leu391AspfsTer105) ([PMID:33719352]). All variants are absent from large population databases, consistent with a recessive loss-of-function mechanism. No recurrent or founder alleles have been reported to date.

These variants segregate with disease in consanguineous and non-consanguineous families, each patient presenting with classical PCD features: chronic sinusitis (HP:0011109), bronchiectasis (HP:0002110), ciliary dyskinesia (HP:0012265), situs inversus totalis (HP:0001696), and male or female infertility (HP:0003251).

Functional assays and domain analyses demonstrate that CCDC151 is required for outer dynein arm assembly. A novel frameshift variant (c.1166_1169dupAGAC) disrupts the third coiled-coil domain, predicting loss of dynein arm docking ([PMID:33719352]).

In vivo studies in Odad3 knockout mice recapitulate human PCD phenotypes, including hydrocephalus, left–right asymmetry defects, and infertility due to absent or malformed spermatozoa ([PMID:38920681]). Conditional adult deletion yields asthenoteratozoospermia and multiple morphological abnormalities of the sperm flagella, confirming dosage sensitivity.

No conflicting evidence has been identified. The convergence of consistent biallelic truncating variants in independent families, absence in controls, detailed segregation, and robust concordant animal models supports a strong gene–disease relationship.

Key Take-home: Biallelic loss-of-function variants in CCDC151 cause autosomal recessive primary ciliary dyskinesia, and genetic testing of CCDC151 informs diagnosis, counseling, and potential gene-targeted therapies.

References

• Bioscience Reports • 2020 • Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome. PMID:32490514
• Human Mutation • 2014 • Nonsense mutation in coiled-coil domain containing 151 gene (CCDC151) causes primary ciliary dyskinesia. PMID:25224326
• Journal of Human Genetics • 2019 • Whole-exome sequencing identifies a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient with primary ciliary dyskinesia and situs inversus. PMID:30504913
• Frontiers in Genetics • 2021 • Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia. PMID:33719352
• Cells • 2024 • The Odad3 Gene Is Necessary for Spermatozoa Development and Male Fertility in Mice. PMID:38920681

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