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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 5, November, 2001 577-583

Germline Mutations in an Intermediate Chain Dynein Cause Primary Ciliary Dyskinesia

Maimoona Zariwala,* Peadar G. Noone,* Aruna Sannuti, Susan Minnix, Zhaoqing Zhou, Margaret W. Leigh, Milan Hazucha, Johnny L. Carson, and Michael R. Knowles

Departments of Medicine and Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder caused by abnormal ciliary ultrastructure and function, characterized clinically by oto-sino-pulmonary disease. Mutations in an intermediate chain dynein (DNAI1; IC78) have recently been described in PCD patients, with outer dynein arm (ODA) defects. The aims of the current study were to test for novel DNAI1 mutations in 13 PCD patients with ODA defects (from 7 unrelated families) and to assess genotype/phenotype correlations in patients and family members. A previously reported mutation (219+3insT) was detected in three PCD patients from two families. The opposite allele had the novel missense mutation G1874C (W568S) in both affected individuals from one family, and a nonsense mutation G1875A (W568X) in an affected individual from another family. The tryptophan at position 568 is a highly conserved residue in the WD-repeat region, and a mutation is predicted to lead to abnormal folding of the protein and loss of function. None of these mutations were found in 32 other PCD patients with miscellaneous ciliary defects. Mutations in DNAI1 are causative for PCD with ODA defects, and are likely the genetic origin of clinical disease in some PCD patients with ultrastructural defects in the ODA.

Abbreviations: base pair, bp; chest radiograph, CXR; aspartic acid, D; denaturing high performance liquid chromatography, DHPLC; dynein intermediate chain 1, DNAI1; diagnosis, DX; forced expiratory volume in 1 s, FEV1; female, F; glycine, G; histidine, H; inner dynein arm, IDA; male, M; nitric oxide, NO; outer dynein arm, ODA; primary ciliary dyskinesia, PCD; polymerase chain reaction, PCR; serine, S; standard error of the mean, SEM; single nucleotide polymorphism, SNP; situs inversus, SI; tryptophan, W; University of North Carolina, UNC; wild type, WT.
* These authors performed equal amounts of work for the study.




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