Population and disease-based prevalence of the common mutations associated with surfactant deficiency.
The prevalence of the common mutations in the surfactant protein-B (121ins2), surfactant protein-C (I73T), and ATP-binding cassette member A3 (E292V) genes in population-based or case-control cohorts of newborn respiratory distress syndrome (RDS) is unknown. We determined the frequencies of these mutations in ethnically diverse population and disease-based cohorts using restriction enzyme analysis (121ins2 and E292V) and a 5' nuclease assay (I73T) in DNA samples from population-based cohorts in Missouri, Norway, South Korea, and South Africa, and from a case-control cohort of newborns with and without RDS (n = 420). We resequenced the ATP-binding cassette member A3 gene (ABCA3) in E292V carriers and computationally inferred ABCA3 haplotypes. The population-based frequencies of 121ins2, E292V, and I73T were rare (<0.4%). E292V was present in 3.8% of newborns with RDS, a 10-fold greater prevalence than in the Missouri cohort (p < 0.001). We did not identify other loss of function mutations in ABCA3 among patients with E292V that would account for their RDS. E292V occurred on a unique haplotype that was derived from a recombination of two common ABCA3 haplotypes. E292V was over-represented in newborns with RDS suggesting that E292V or its unique haplotype impart increased genetic risk for RDS.
Garmany
Tami H
TH
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Wambach
Jennifer A
JA
Heins
Hillary B
HB
Watkins-Torry
Julie M
JM
Wegner
Daniel J
DJ
Bennet
Kate
K
An
Ping
P
Land
Garland
G
Saugstad
Ola D
OD
Henderson
Howard
H
Nogee
Lawrence M
LM
Cole
F Sessions
FS
Hamvas
Aaron
A
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007723:Korea; D008297:Male; D008923:Missouri; D009154:Mutation; D009664:Norway; D011159:Population Surveillance; D037701:Pulmonary Surfactant-Associated Protein B / Q000172:deficiency / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000172:deficiency / Q000235:genetics*; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013019:South Africa
C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human