Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Issue 5 (18th December 2011)

• Record Type: Journal Article
• Authors: Knowles, Michael R; Leigh, Margaret W; Carson, Johnny L; Davis, Stephanie D; Dell, Sharon D; Ferkol, Thomas W; Olivier, Kenneth N; Sagel, Scott D; Rosenfeld, Margaret; Burns, Kimberlie A; Minnix, Susan L; Armstrong, Michael C; Lori, Adriana; Hazucha, Milan J; Loges, Niki T; Olbrich, Heike; Becker-Heck, Anita; Schmidts, Miriam; Werner, Claudius; Omran, Heymut; Zariwala, Maimoona A
• Is Part Of: Thorax. Volume 67:Issue 5(2012)
• Page Start: 433
• Page End: 441
• Publication Date: 2011-12-18
• Subjects: Cilia -- dynein -- Kartagener syndrome -- dextrocardia -- heterotaxy -- airway epithelium -- atypical mycobacterial infection -- bacterial infection -- cystic fibrosis -- infection control -- nebuliser therapy -- rare lung diseases -- respiratory infection -- bronchiectasis -- paediatric lung disaese -- histology/cytology -- tobacco and the lung -- paediatric physician -- respiratory measurement -- asthma -- asthma epidemiology -- clinical epidemiology -- paediatric asthma -- lung proteases -- asthma genetics -- lung physiology; Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thoraxjnl-2011-200301
• Languages: English
• ISSNs: 0040-6376

Abstract

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.