DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects.
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.
Hornef
Nada
N
Department of Pediatrics and Adolescent Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany.
Olbrich
Heike
H
Horvath
Judit
J
Zariwala
Maimoona A
MA
Fliegauf
Manfred
M
Loges
Niki Tomas
NT
Wildhaber
Johannes
J
Noone
Peadar G
PG
Kennedy
Marcus
M
Antonarakis
Stylianos E
SE
Blouin
Jean-Louis
JL
Bartoloni
Lucia
L
Nüsslein
Thomas
T
Ahrens
Peter
P
Griese
Matthias
M
Kuhl
Heiner
H
Sudbrak
Ralf
R
Knowles
Michael R
MR
Reinhardt
Richard
R
Omran
Heymut
H
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
D056444:Axonemal Dyneins; C497507:DNAH5 protein, human; D004398:Dyneins