DNAH5 Mutations Are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects

Abstract

Rationale: 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. Highresolution 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 (IVS75-2AϾT, IVS76ϩ5GϾA). In a preselected subpopulation with documented outer dynein arm defects (n ϭ 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.

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children

“…It is the human orthologue of the Chlamydomonas c-heavy chain gene, the mutants of which are slow-swimming algae with ultrastructural ODA defects [18,33]. Mutations in human DNAH5 are regularly associated with ODA defects, random left-right asymmetry and male infertility [18,34,35]. The mutational prevalence of DNAH5 is currently known in a total of 134 PCD families [18,35].…”

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

“…For nNO validation studies at six (non-UNC) sites, PCD was confirmed by PCD-specific ciliary EM defects and, by the presence of biallelic mutations in PCD genes (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Informed consent was obtained at the University of North Carolina at Chapel Hill and collaborating institutions under the auspices of Committees on the Protection of the Rights of Human Subjects.…”

Ultrastructure of Spermatozoa from Infertility Patients

“…The DNAH5 product is a major motor protein of outer dynein arms. Its mutations were observed in more than 25% of PCD patients [98].…”