Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia

doi:10.1073/pnas.152337699

Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia

^*Division of Medical Genetics, University of Geneva Medical School, and University Hospitals, 1211 Geneva 4, Switzerland; Departments of^† Molecular and Human Genetics and of^∥ Pediatrics, Baylor College of Medicine, Houston, TX 77030; ^‡Departments of Human Genetics and Ear, Nose, and Throat, University Hospital of Leuven, B-3000 Leuven, Belgium;^§ Otorhinolaryngology Service, General and University Hospital, Valencia E-46014, Spain; and ^¶Department of Pediatrics and Child Health, Royal Free and University College Medical School, University College London, London NW3 2QG, United Kingdom

Communicated by Victor A. McKusick, Johns Hopkins University School of Medicine, Baltimore, MD (received for review March 18, 2002)

Abstract

Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv/iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

Footnotes

↵ ** To whom reprint requests should be addressed. E-mail: stylianos.antonarakis{at}medecine.unige.ch.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. ).
↵ †† Bartoloni, L., Mitchison, H. M., Pazour, G. J., Maiti, A. K., Meeks, M., Chung, E., Dickert, B. L., Spiden, S., Gehrig, C., Rossier, C., et al. (2000) Eur. J. Hum. Genet. 8, Suppl. 1 (abstr.).
Abbreviations:
1. AAA, ATPases associated diverse cellular A domains
2. RACE, rapid amplification of cDNA ends
3. UPD, uniparental disomy
4. CFTR, cystic fibrosis transmembrane conductance regulator
5. RT, reverse transcription