Mutations of DNAI1 in Primary Ciliary Dyskinesia Evidence of Founder Effect in a Common Mutation

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 mutationshave been reported in DNAI1 and DNAH5 encoding outer dyneinarm (ODA) proteins of cilia. Objectives: We analyzed DNAI1 to identify disease-causing mutationsin PCD and to determine if the previously reported IVS1+2_3insT (219+3insT) mutationrepresents 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: Mutationsin DNAI1 including 12 novel mutationswere identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutationswere not identified by reverse transcriptase–polymerase chain reaction. The prevalence of mutationsin families with defined ODA defect was 13%; no mutationswere found in patients without a defined ODA defect. The previously reported IVS1+2_3insT mutationaccounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutationsoccurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging as mutationclusters harboring 29% (12/42) of mutant alleles. Conclusions: A total of 10% of patients with PCD are estimated to harbor mutationsin 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.