PUBLICATION

CCDC151 Mutations Cause Primary Ciliary Dyskinesia by Disruption of the Outer Dynein Arm Docking Complex Formation

Authors

Hjeij, R., Onoufriadis, A., Watson, C.M., Slagle, C.E., Klena, N.T., Dougherty, G.W., Kurkowiak, M., Loges, N.T., Diggle, C.P., Morante, N.F., Gabriel, G.C., Lemke, K.L., Li, Y., Pennekamp, P., Menchen, T., Konert, F., Marthin, J.K., Mans, D.A., Letteboer, S.J., Werner, C., Burgoyne, T., Westermann, C., Rutman, A., Carr, I.M., O'Callaghan, C., Moya, E., Chung, E.M., UK10K Consortium, Sheridan, E., Nielsen, K.G., Roepman, R., Bartscherer, K., Burdine, R.D., Lo, C.W., Omran, H., Mitchison, H.M.

ID

ZDB-PUB-140906-2

Date

2014

Source

American journal of human genetics 95: 257-274 (Journal)

Registered Authors

Burdine, Rebecca, Lo, Cecilia, Slagle, Christopher

Keywords

none

MeSH Terms

Animals
Axonemal Dyneins/genetics
Axonemal Dyneins/metabolism*
Axoneme/genetics
Cells, Cultured
Cilia/metabolism
Cilia/pathology*
Embryo, Mammalian/cytology
Embryo, Mammalian/metabolism
Exome/genetics
Female
Fluorescent Antibody Technique
Humans
Immunoblotting
Immunoprecipitation
In Situ Hybridization
Kartagener Syndrome/genetics*
Kartagener Syndrome/metabolism
Kartagener Syndrome/pathology
Male
Mice
Mice, Knockout
Microtubule-Associated Proteins/genetics
Microtubule-Associated Proteins/metabolism
Microtubule-Associated Proteins/physiology*
Mutation/genetics*
Pedigree
Phenotype
Two-Hybrid System Techniques
Zebrafish/genetics
Zebrafish/growth & development
Zebrafish/metabolism

PubMed

25192045 Full text @ Am. J. Hum. Genet.

Abstract

A diverse family of cytoskeletal dynein motors powers various cellular transport systems, including axonemal dyneins generating the force for ciliary and flagellar beating essential to movement of extracellular fluids and of cells through fluid. Multisubunit outer dynein arm (ODA) motor complexes, produced and preassembled in the cytosol, are transported to the ciliary or flagellar compartment and anchored into the axonemal microtubular scaffold via the ODA docking complex (ODA-DC) system. In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality. Here, by combined high-throughput mapping and sequencing, we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families whose cilia showed a complete loss of ODAs and severely impaired ciliary beating. Consistent with the laterality defects observed in these individuals, we found Ccdc151 expressed in vertebrate left-right organizers. Homozygous zebrafish ccdc151(ts272a) and mouse Ccdc151(Snbl) mutants display a spectrum of situs defects associated with complex heart defects. We demonstrate that CCDC151 encodes an axonemal coiled coil protein, mutations in which abolish assembly of CCDC151 into respiratory cilia and cause a failure in axonemal assembly of the ODA component DNAH5 and the ODA-DC-associated components CCDC114 and ARMC4. CCDC151-deficient zebrafish, planaria, and mice also display ciliary dysmotility accompanied by ODA loss. Furthermore, CCDC151 coimmunoprecipitates CCDC114 and thus appears to be a highly evolutionarily conserved ODA-DC-related protein involved in mediating assembly of both ODAs and their axonemal docking machinery onto ciliary microtubules.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Mutations / Transgenics

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Hjeij et al., 2014 ZDB-PUB-140906-2 PMID:25192045

CCDC151 Mutations Cause Primary Ciliary Dyskinesia by Disruption of the Outer Dynein Arm Docking Complex Formation

Hjeij et al., 2014

ZDB-PUB-140906-2
PMID:25192045