The genetic advantage hypothesis in cystic fibrosis heterozygotes: a murine study.
1. The delta F508 mutation of the cystic fibrosis (CF) gene is of high frequency in man (1 in 25) and in homozygotes causes cystic fibrosis. It is suggested that cystic fibrosis heterozygotes withstand secretory diarrhoea better than normal individuals and so are genetically advantaged. This hypothesis has been examined by measuring electrogenic chloride secretion in gut epithelia of normal and heterozygous CF mice. 2. Chloride secretory responses of normal and heterozygous colonic epithelia to forskolin, vasoactive intestinal polypeptide (VIP), isoprenaline, cholera toxin, heat-stable enterotoxin (STa), guanylin, carbachol and lysylbradykinin were examined. No significant differences in responses of tissues of the two genotypes were found. 3. Responses of normal and heterozygous ileal epithelia to forskolin and glucose were investigated. Heterozygous tissues responded as well as normal tissues. 4. Frusemide (furosemide) caused virtually identical inhibition of the chloride secretory responses to forskolin in colonic epithelia of both genotypes. 5. No evidence to support the genetic advantage hypothesis in ileal or colonic epithelia of the null CF mouse has been found, at least for acute responses. If the hypothesis is true then either (a) other non-cystic fibrosis transmembrane conductance regulator (non-CFTR) transport processes are involved, (b) prolonged exposure to secretagogues is required, or (c) delta F508 CFTR is responsible for the protective effect.
Cuthbert
A W
AW
Department of Pharmacology, University of Cambridge, UK.
Halstead
J
J
Ratcliff
R
R
Colledge
W H
WH
Evans
M J
MJ
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000737:chemistry / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics*; D004768:Enterotoxins / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D029968:Escherichia coli Proteins; D005665:Furosemide / Q000494:pharmacology; D005768:Gastrointestinal Hormones; D005947:Glucose / Q000494:pharmacology; D006579:Heterozygote; D007082:Ileum / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D007609:Kallidin / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D045265:Natriuretic Peptides; D010455:Peptides / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D001427:Bacterial Toxins; D018118:Chloride Channels; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; C034151:heat stable toxin (E coli); C072685:guanylin; D005576:Colforsin; D007609:Kallidin; D014660:Vasoactive Intestinal Peptide; D005665:Furosemide; D002217:Carbachol; D002772:Cholera Toxin; D000242:Cyclic AMP; D005947:Glucose; D007545:Isoproterenol; D002118:Calcium