title: Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 as mutation clusters harboring 29% (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.
authors.affiliation: 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
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Franck
authors.initials: F
authors.lastname: Ceppa
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Kennedy
authors.forename: Peadar G
authors.initials: PG
authors.lastname: Noone
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Hazucha
authors.forename: Adriana
authors.initials: A
authors.lastname: Lori
authors.forename: Judit
authors.initials: J
authors.lastname: Horvath
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bridoux
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pennarun
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Duriez
authors.forename: Estelle
authors.initials: E
authors.lastname: Escudier
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Rahul
authors.initials: R
authors.lastname: Chodhari
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Morgan
authors.forename: Robbert U
authors.initials: RU
authors.lastname: de Iongh
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rutland
authors.forename: Ugo
authors.initials: U
authors.lastname: Pradal
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D056444:Axonemal Dyneins; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004398:Dyneins / Q000235:genetics*; D005091:Exons; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: C425071:DNAI1 protein, human; D004247:DNA; D056444:Axonemal Dyneins; D004398:Dyneins