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Gene discovery for motile cilia disorders: mutation spectrum in primary ciliary dyskinesia and discovery of mutations in CCDC151

  • A Onoufriadis1,
  • R Hjeij2,
  • CM Watson3,
  • CE Slagle4,
  • NT Klena5,
  • GW Dougherty2,
  • M Kurkowiak2,
  • NT Loges2,
  • CP Diggle3,
  • NF Morante4,
  • GC Gabriel5,
  • KL Lemke5,
  • Y Li5,
  • P Pennekamp2,
  • T Menchen2,
  • JK Marthin6,
  • D Mans7,
  • SJ Letteboer7,
  • C Werner2,
  • T Burgoyne8,
  • C Westermann2,
  • A Rutman9,
  • IM Carr3,
  • C O'Callaghan9, 10,
  • E Moya11,
  • EMK Chung10,
  • UK10K12,
  • E Sheridan3,
  • KG Nielsen6,
  • R Roepman7,
  • RD Burdine4,
  • CW Lo5,
  • H Omran2 and
  • H Mitchison10
Cilia20154(Suppl 1):P30

Published: 13 July 2015


Exome SequencingPrimary Ciliary DyskinesiaDocking ComplexComplex MachineryTruncate Variant

We present a stratification of the genetic basis of primary ciliary dyskinesia (PCD), based on screening >230 individuals for gene mutations using various approaches including whole exome sequencing. PCD is a genetically heterogeneous recessive ciliopathy, characterized by chronic lung disease and laterality and fertility defects arising from cilia and sperm dysmotility. Most PCD is caused by loss of the ciliary outer dynein arm motors (ODA) essential for motility, arising from mutations in ODA subunits or ODA docking and targeting proteins. Gene panel resequencing of candidate ciliopathy genes in affected children from a consanguineous Bedouin-Arabic family has recently revealed a homozygous protein truncating variant in CCDC151 (c.925G>T; p.Glu308*). Parallel exome sequencing combined with autozygosity mapping in a consanguineous UK-Pakistani-origin family highlighted a large autozygous region on chr 19p13 harbouring a homozygous CCDC151 protein-truncating variant (c.1256C>T; pSer419*). Sanger sequencing of CCDC151 in 150 more PCD cases identified another individual carrying c.925G>T. Transmission electron microscopy of respiratory cilia from individuals carrying CCDC151 mutations showed loss of ODA. Consistent with laterality defects in these individuals, we find Ccdc151 expressed in vertebrate left-right organizers. Both homozygous zebrafish and mouse Ccdc151-deficient mutants display situs defects associated with complex heart defects. Immunofluorescence analysis in patients shows that CCDC151 mutations abolish assembly of CCDC151 into respiratory cilia, and furthermore cause a failure in assembly of the ODA component DNAH5 and ODA docking proteins CCDC114 and ARMC4. We conclude that CCDC151 mutations appear to cause PCD by disruption of the axonemal ODA docking complex machinery.

Authors’ Affiliations

Kings College London, London, UK
University Children's Hospital Muenster, Muenster, Germany
University of Leeds, Leeds, UK
Princeton University, Princeton, USA
University of Pittsburgh, Pittsburgh, USA
Copenhagen University Hospital, Copenhagen, Denmark
Radboud University Medical Center, Nijmegen, The Netherlands
UCL Institute of Ophthalmology, London, UK
University of Leicester, Leicester, UK
UCL Institute of Child Health, London, UK
Bradford Royal Infirmary, Bradford, UK
(12), Cambridge, UK


© Onoufriadis et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.