• Maimoona A Zariwala, Margaret W Leigh, Franck Ceppa, Marcus P Kennedy, Peadar G Noone, Johnny L Carson, Milan J Hazucha, Adriana Lori, Judit Horvath, Heike Olbrich, Niki T Loges, Anne-Marie Bridoux, Gaëlle Pennarun, Bénédicte Duriez, Estelle Escudier, Hannah M Mitchison, Rahul Chodhari, Eddie M K Chung, Lucy C Morgan, Robbert U de Iongh, Jonathan Rutland, Ugo Pradal, Heymut Omran, Serge Amselem, and Michael R Knowles.
• University of North Carolina at Chapel Hill 27599-7248, USA, and Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Germany. zariwala@med.unc.edu
• Am. J. Respir. Crit. Care Med. 2006 Oct 15; 174 (8): 858-66.

RationalePrimary 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.ObjectivesWe 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.MethodsPatients 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.ResultsMutations 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.ConclusionsA 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.

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