Published ahead of print on July 20, 2006, doi:10.1164/rccm.200603-370OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200603-370OC
Mutations of DNAI1 in Primary Ciliary DyskinesiaEvidence of Founder Effect in a Common MutationUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Institut de la Santé et de la Recherche Médicale, Créteil, France; Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany; Royal Free and University College Medical School, London, United Kingdom; Concord Hospital, Sydney; Anatomy & Cell Biology, University of Melbourne, Melbourne, Australia; and Cystic Fibrosis Center, Verona, Italy Correspondence and requests for reprints should be addressed to Maimoona Zariwala, Ph.D., F.A.C.M.G., The University of North Carolina at Chapel Hill, Department of Pathology and Laboratory Medicine, CB# 7248, 7123 Thurston-Bowles Bldg., Chapel Hill, NC 27599-7248. E-mail: zariwala{at}med.unc.edu Rationale: Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive, genetic disorder characterized by ciliary dysfunction, sino-pulmonary disease, and situs inversus. Disease-causing mutations have been reported in DNAI1 and DNAH5 encoding outer dynein arm (ODA) proteins of cilia. Objectives: We analyzed DNAI1 to identify disease-causing mutations in PCD and to determine if the previously reported IVS1+2_3insT (219+3insT) mutation represents a "founder" or "hot spot" mutation. Methods: Patients with PCD from 179 unrelated families were studied. Exclusion mapping showed no linkage to DNAI1 for 13 families; the entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed on nasal epithelial RNA in 14 families. Results: Mutations in DNAI1 including 12 novel mutations were identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutations were not identified by reverse transcriptase–polymerase chain reaction. The prevalence of mutations in families with defined ODA defect was 13%; no mutations were found in patients without a defined ODA defect. The previously reported IVS1+2_3insT mutation accounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutations occurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging as mutation clusters harboring 29% (12/42) of mutant alleles. Conclusions: A total of 10% of patients with PCD are estimated to harbor mutations in DNAI1; most occur as a common founder IVS1+2_3insT or in exons 13, 16, and 17. This information is useful for establishing a clinical molecular genetic test for PCD.
Key Words: cilia • dynein • dextrocardia • Kartagener syndrome • mutation This article has been cited by other articles:
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