Primary ciliary dyskinesia

Abbreviations: ODA = outer dynein arm; PCD = primary cilliary dyskinesia

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder that is caused by abnormal ciliary ultrastructure and function, and is characterized by defective mucociliary clearance and bronchiectasis. The genetics of PCD are largely unknown and are important because diagnosis may be difficult and the disease may be more common than currently appreciated. Two loss-of-function mutations in an intermediate chain dynein (IC78), that is, DNAI1, have been reported (1) in a PCD patient who was lacking ciliary outer dynein arms (ODAs). From a large cohort of PCD families (22; 44 patients) at the University of North Carolina, we selected seven unrelated families in whom there were 13 subjects (7 men) with PCD and clear-cut defects in the ODAs to attempt to identify mutations in the DNAI1 gene.

To precisely define the phenotype, a rigorous clinical evaluation was performed, including a directed medical history (for the presence of sinopulmonary disease, recurrent otitis media, and neonatal respiratory distress), a physical examination (including situs inversus), measures of nasal nitric oxide levels, and nasal ciliary ultrastructure studies. Patients were categorized as having abnormalities of the inner dynein arms, the ODAs, or both dynein arms. The identification of intragenic polymorphisms (to establish the linkage) followed by direct DNA sequencing were the methods of choice for defining genetics.

In two families, we identified a previously reported splice mutation (insertion of thymine at the + 3 position of intron 1 of the DNAI1 gene) in one allele of the three PCD patients. We further identified two novel mutations in the second allele at codon 568 (exon 17) that were associated with PCD patients in both the families. One family (two patients, one with situs inversus) had a G1874C transversion leading to a missense mutation (W568S). The other family (one patient) had a G1875A transition leading to a nonsense (W568X) mutation. In one family, there was an unaffected sibling carrier. Both of these mutations were present at the conserved tryptophane residue in the WD-repeat region of the gene, which is predicted to lead to abnormal folding of the DNAI1 protein. The finding suggests that this location may be a potentially common site for recessive mutations that are associated with PCD and clinical disease.

REFERENCE

(1) Pennarun G, Escudier E, Chapelin C, et al. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet 1999; 65:1508-1519

* From the Pulmonary/Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Supported by grants from the American College of Chest Physicians and the American Lung Association of North Carolina, and by National Institutes of Health grants RR00046 and HL04225.

Correspondence to: Peadar G. Noone, MD, Division of Pulmonary/Critical Care Medicine, CB 7248, 7123 Thurston Bowles, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248; e-mail: pnoone@med.unc.edu

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2002 Gale Group