Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation

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 IonghJonathan Rutland, Ugo Pradal, Heymut Omran, Serge Amselem, Michael R. Knowles

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

151 Citations (Scopus)


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 asmutation clusters harboring29%(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.

Original languageEnglish
Pages (from-to)858-866
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number8
Publication statusPublished - 15 Oct 2006


  • Cilia
  • Dextrocardia
  • Dynein
  • Kartagener syndrome
  • Mutation


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