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Thorax 67:433-441 doi:10.1136/thoraxjnl-2011-200301
  • Respiratory research
  • Original article

Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure

  1. for the Genetic Disorders of Mucociliary Clearance Consortium
  1. 1Department of Medicine, UNC School of Medicine, Chapel Hill, North Carolina, USA
  2. 2Department of Pediatrics, UNC School of Medicine, Chapel Hill, North Carolina, USA
  3. 3Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
  4. 4Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
  5. 5Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  6. 6Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
  7. 7Children's Hospital and Regional Medical Center, Seattle, Washington, USA
  8. 8Department of Pediatrics and Adolescent Medicine, University Hospital, Freiburg, Germany
  9. 9Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin—Allgemeine Pädiatrie, Münster, Germany
  10. 10Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany
  11. 11Department of Pathology and Lab Medicine, UNC School of Medicine, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr Michael R Knowles, University of North Carolina, Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, CB# 7248, 7123 Thurston-Bowles Bldg, Chapel Hill, NC 27599-7248, USA; knowles{at}med.unc.edu
  1. Contributors All authors have contributed substantively to this work and have approved the final manuscript for submission.

  • Received 5 April 2011
  • Accepted 4 November 2011
  • Published Online First 18 December 2011

Abstract

Rationale Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11).

Objectives To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology.

Methods 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.

Results Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations.

Conclusions Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.

Footnotes

  • See Editorial, p 377

  • Funding MRK, MWL, JLC, MJH, SLM, SDD, TWF, KNO, SDS, MR, KEB, MCA, AL and MAZ are supported by National Institute of Health research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by ORDR and NHLBI, NIH. MRK and MAZ are supported by National Institutes of Health grant 5 R01HL071798. TWF is supported by R01 HL08265 and Children's Discovery Institute. KNO is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. JLC is supported by Clinical Innovator Award by Flight Attendant Medical Research Institute. HO is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Om 6/4, GRK1104, SFB592). Resequencing was provided by the University of Washington, Department of Genome Sciences, under US Federal government contract number N01-HV-48194 from National Heart, Lung, and Blood Institute. This work was supported in part by grants RR00046, UL1 RR025747 and UL1 RR025780 from the National Center of Research Resources, NHLBI P01 HL034322, NIH and CFF R026-CR07. This consortium, Genetic Disorders of Mucociliary Clearance is part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project was provided by grant 5 U54 HL096458-06 from the NHLBI and the NIH Office of Rare Diseases Research (ORDR). The views expressed do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organisations imply endorsement by the U.S government.

  • Competing interests The first and the last authors are part of the patent for DNAH11 gene mutations.

  • Ethics approval IRB at the University of North Carolina.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We will abide by the data-sharing policy of the journal.

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