Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation.
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.
Zariwala
Maimoona A
MA
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
Leigh
Margaret W
MW
Ceppa
Franck
F
Kennedy
Marcus P
MP
Noone
Peadar G
PG
Carson
Johnny L
JL
Hazucha
Milan J
MJ
Lori
Adriana
A
Horvath
Judit
J
Olbrich
Heike
H
Loges
Niki T
NT
Bridoux
Anne-Marie
AM
Pennarun
Gaëlle
G
Duriez
Bénédicte
B
Escudier
Estelle
E
Mitchison
Hannah M
HM
Chodhari
Rahul
R
Chung
Eddie M K
EM
Morgan
Lucy C
LC
de Iongh
Robbert U
RU
Rutland
Jonathan
J
Pradal
Ugo
U
Omran
Heymut
H
Amselem
Serge
S
Knowles
Michael R
MR
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
C425071:DNAI1 protein, human; D004247:DNA; D056444:Axonemal Dyneins; D004398:Dyneins