Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus.
The glycine-to-aspartic acid missense mutation at codon 551 (G551D), which is within the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator (CFTR), is the third most common cystic fibrosis (CF) mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta F508, the most common CF mutation, we studied 79 compound heterozygotes for G551D/delta F508, from nine centers in Europe and North America. Each subject was matched, by age and sex, with a delta F508 homozygote from the same center. A retrospective cohort analysis was performed on the following outcome parameters: age at diagnosis, sweat chloride, meconium ileus at birth, height, weight, weight for height, FVC, FEV1, chest X-ray score, pseudomonas colonization, pancreatic sufficiency, and Shwachman clinical score. There was less meconium ileus among the G551D/delta F508 compound heterozygotes (relative risk 0.33; 95% confidence interval .13-.86), as well as a trend toward later age at diagnosis of pancreatic insufficiency. No statistically significant difference was found between the groups for any other parameter. These results suggest that the CF genotype can be a predictor of pancreatic and intestinal phenotype. Prenatal counseling for the two genotype groups should differ only with respect to probability of meconium ileus. Clinical outcome (after survival of meconium ileus) for G551D/delta F508 compound heterozygotes and delta F508 homozygotes is indistinguishable; therefore, prognostic counseling should not differ.
Hamosh
A
A
Center for Medical Genetics, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD.
King
T M
TM
Rosenstein
B J
BJ
Corey
M
M
Levison
H
H
Durie
P
P
Tsui
L C
LC
McIntosh
I
I
Keston
M
M
Brock
D J
DJ
D000293:Adolescent; D001224:Aspartic Acid / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003062:Codon; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005998:Glycine / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007415:Intestinal Obstruction / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D008470:Meconium; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D012307:Risk Factors
C505032:CFTR protein, human; D003062:Codon; D008565:Membrane Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D001224:Aspartic Acid; D005998:Glycine