title: Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure.
abstract: BACKGROUND
  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).
  
  
  OBJECTIVE
  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.
authors.affiliation: 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@med.unc.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Davis
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Ferkol
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Kimberlie A
authors.initials: KA
authors.lastname: Burns
authors.forename: Susan L
authors.initials: SL
authors.lastname: Minnix
authors.forename: Michael C
authors.initials: MC
authors.lastname: Armstrong
authors.forename: Adriana
authors.initials: A
authors.lastname: Lori
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Hazucha
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Anita
authors.initials: A
authors.lastname: Becker-Heck
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
mesh_terms: D000293:Adolescent; D000328:Adult; D056444:Axonemal Dyneins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000648:ultrastructure*; D002925:Ciliary Motility Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D056444:Axonemal Dyneins; C465433:DNAH11 protein, human