title: DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects.
abstract: BACKGROUND
  Primary ciliary dyskinesia (PCD) is characterized by recurrent airway infections and randomization of left-right body asymmetry. To date, autosomal recessive mutations have only been identified in a small number of patients involving DNAI1 and DNAH5, which encode outer dynein arm components.
  
  
  METHODS
  We screened 109 white PCD families originating from Europe and North America for presence of DNAH5 mutations by haplotype analyses and/or sequencing.
  
  
  RESULTS
  Haplotype analyses excluded linkage in 26 families. In 30 PCD families, we identified 33 novel (12 nonsense, 8 frameshift, 5 splicing, and 8 missense mutations) and two known DNAH5 mutations. We observed clustering of mutations within five exons harboring 27 mutant alleles (52%) of the 52 detected mutant alleles. Interestingly, 6 (32%) of 19 PCD families with DNAH5 mutations from North America carry the novel founder mutation 10815delT. Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects. High-resolution immunofluorescence imaging of respiratory epithelial cells from eight patients with DNAH5 mutations showed mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers. Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients and remained detectable in the proximal ciliary axoneme in one patient carrying compound heterozygous splicing mutations at the 3'-end (IVS75-2A>T, IVS76+5G>A). In a preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients.
  
  
  CONCLUSIONS
  DNAH5 is frequently mutated in patients with PCD exhibiting outer dynein arm defects and mutations cluster in five exons.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany.
authors.forename: Nada
authors.initials: N
authors.lastname: Hornef
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Judit
authors.initials: J
authors.lastname: Horvath
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.forename: Niki Tomas
authors.initials: NT
authors.lastname: Loges
authors.forename: Johannes
authors.initials: J
authors.lastname: Wildhaber
authors.forename: Peadar G
authors.initials: PG
authors.lastname: Noone
authors.forename: Marcus
authors.initials: M
authors.lastname: Kennedy
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Blouin
authors.forename: Lucia
authors.initials: L
authors.lastname: Bartoloni
authors.forename: Thomas
authors.initials: T
authors.lastname: Nüsslein
authors.forename: Peter
authors.initials: P
authors.lastname: Ahrens
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Heiner
authors.initials: H
authors.lastname: Kuhl
authors.forename: Ralf
authors.initials: R
authors.lastname: Sudbrak
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D056444:Axonemal Dyneins; D004252:DNA Mutational Analysis; D004398:Dyneins / Q000235:genetics* / Q000648:ultrastructure*; D005455:Fluorescent Antibody Technique; D006239:Haplotypes; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D056444:Axonemal Dyneins; C497507:DNAH5 protein, human; D004398:Dyneins