Splice-Site Mutations in the Axonemal Outer Dynein Arm Docking Complex Gene CCDC114 Cause Primary Ciliary Dyskinesia

Alexandros Onoufriadis,Tamara Paff,Dinu Antony,Amelia Shoemark,Dimitra Micha,Bertus Kuyt,Miriam Schmidts,Stavroula Petridi,Jeanette E Dankert-Roelse,Eric G Haarman,Johannes M.A Daniels,Richard D Emes,Robert Wilson,Claire Hogg,Peter J Scambler,Eddie M.K Chung,Gerard Pals,Hannah M Mitchison

doi:10.1016/j.ajhg.2012.11.002

Abstract

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating. Here, we identify loss-of-function mutations in CCDC114 causing PCD with laterality malformations involving complex heart defects. CCDC114 is homologous to DCC2, an ODA microtubule-docking complex component of the biflagellate alga Chlamydomonas. We show that CCDC114 localizes along the entire length of human cilia and that its deficiency causes a complete absence of ciliary ODAs, resulting in immotile cilia. Thus, CCDC114 is an essential ciliary protein required for microtubular attachment of ODAs in the axoneme. Fertility is apparently not greatly affected by CCDC114 deficiency, and qPCR shows that this may explained by low transcript expression in testis compared to ciliated respiratory epithelium. One CCDC114 mutation, c.742G>A, dating back to at least the 1400s, presents an important diagnostic and therapeutic target in the isolated Dutch Volendam population.

Highlights

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating
Ineffective mucociliary clearance caused by respiratory epithelial cilia dysmotility gives rise to chronic, destructive upper and lower airway disease manifesting with recurrent respiratory infections, chronic sinusitis, and otitis media, usually evident from the first year of life and progressing to permanent lung damage.[4,9]
Loss of the outer dynein arms is the most common ciliary defect observed in PCD (>65% of cases), caused by mutations in ODA components (DNAH5 [MIM 603335], DNAI1 [MIM 6043661], DNAI2 [MIM 605483], DNAL1 [MIM 602135], TXNDC3 [MIM 607421])[16,17,18,19,20] or in genes encoding proteins involved in ODA assembly

Summary

REPOR T

Alexandros Onoufriadis,[1,10] Tamara Paff,[2,3,4,10] Dinu Antony,[1] Amelia Shoemark,[5] Dimitra Micha,[2] Bertus Kuyt,[2] Miriam Schmidts,[1] Stavroula Petridi,[1] Jeanette E. We filtered variants for novelty by comparing them to 181 UK10K non-PCD exomes and by excluding those that were present in the 1000 Genomes Project polymorphism database with a minor allele frequency >0.005.34 Because the Volendam population is isolated and the PCD-01 III:[3] individual is the offspring of a consanguineous marriage, we followed a model of rare autosomal-recessive inheritance. CCDC114, located on chromosome 19q13.3, represented an excellent functional candidate, being the human gene orthologous to Chlamydomonas DCC2, which encodes an axonemal outer dynein arm microtubule-docking complex subunit.[35] in situ hybridization images of mouse embryos generated as part of the Eurexpress project and available within the Mouse Genome Informatics pages showed a strong pattern of gene expression in motile ciliated tissues, including the nasal cavity epithelium and brain ventricles.[36] Both affected Volendam. This base change is predicted to cause a frameshift in the CCDC114 protein resulting from loss of the conserved donor splice site

NY dextrocardia

Findings

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