Published ahead of print on July 20, 2006, doi:10.1164/rccm.200603-370OC Am. J. Respir. Crit. Care Med., Volume 174, Number 8, October 2006, 858-866 A more recent version of this article appeared on October 15, 2006
Submitted on March 13, 2006 Mutations of DNAI1 in Primary Ciliary Dyskinesia: Evidence of Founder Effect in a Common MutationMaimoona A Zariwala1*,1 School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 U.654 and U.651, Institut de la Sante et de la Recherche Medicale, Creteil, France, 3 Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany, 4 Royal Free and University College Medical School, London, United Kingdom, 5 Department of Thoracic Medicine, Concord Hospital, Sydney, Australia, 6 Anatomy and Cell Biology, University of Melbourne, Melbourne, Australia, 7 Cystic Fibrosis Center, Verona, Italy, 8 School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; U.654 and U.651, Institut de la Sante et de la Recherche Medicale, Creteil, France * To whom correspondence should be addressed. 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 1) to identify disease-causing mutations in PCD, 2) to determine if previously reported IVS1+2_3insT (219+3insT) mutation represents a 'founder' or 'hot spot' mutation. Methods: PCD patients from 179 unrelated families were ascertained. Exclusion mapping showed no linkage to DNAI1 for 13 families; entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase-PCR (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 RT-PCR. 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: Total of 10% PCD patients are estimated to harbor mutations in DNAI1; most occurring as either a common 'founder' IVS1+2_3insT or in three exons. This information is useful for establishing a clinical molecular genetic test for of PCD. Key words: cilia, dynein, dextrocardia, Kartagener syndrome, mutation.
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