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

• Published in: American journal of respiratory and critical care medicine Vol. 174; no. 8; pp. 858 - 866
• Main Authors: Zariwala, Maimoona A, Leigh, Margaret W, Ceppa, Franck, Kennedy, Marcus P, Noone, Peadar G, Carson, Johnny L, Hazucha, Milan J, Lori, Adriana, Horvath, Judit, Olbrich, Heike, Loges, Niki T, Bridoux, Anne-Marie, Pennarun, Gaelle, Duriez, Benedicte, Escudier, Estelle, Mitchison, Hannah M, Chodhari, Rahul, Chung, Eddie M. K, Morgan, Lucy C, de Iongh, Robbert U, Rutland, Jonathan, Pradal, Ugo, Omran, Heymut, Amselem, Serge, Knowles, Michael R
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.10.2006; American Lung Association; American Thoracic Society
• Subjects: A. Airway Biology; Adolescent; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Axonemal Dyneins; Biological and medical sciences; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Child; Child, Preschool; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA; DNA - genetics; Dyneins; Dyneins - genetics; Exons; Female; Founder Effect; Gene Frequency; Genetics; Genotype; Human genetics; Human health and pathology; Humans; Infant; Intensive care medicine; Kartagener Syndrome; Kartagener Syndrome - genetics; Life Sciences; Male; Medical sciences; Mutation; Pedigree; Pharmacology. Drug treatments; Phenotype; Polymerase Chain Reaction; Pulmonology and respiratory tract; Nervous system diseases; Intensive care; Enzyme; Cardiovascular disease; Dynein ATPase; Kartagener syndrome; Congenital disease; Dextrocardia; Cerebral disorder; Involuntary movement; dynein; Heart disease; Central nervous system disease; Hydrolases; Mutation; Neurological disorder; Resuscitation; Extrapyramidal syndrome; Cilia; Dyskinesia; mutation; cilia; dextrocardia
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200603-370OC

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. 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. 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. 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. 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.