Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model

Gabriel, Sherif E.; Brigman, K; Koller, BH; Boucher, R. C.; Stutts, M. Jackson

doi:10.1126/science.7524148

Cited by 445 publications

(272 citation statements)

References 28 publications

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“…The mutation ΔF508 in Cystic fibrosis also has a high incidence in the Ashkenazi population [52]. This mutation in another ATP transporter was associated with protection against cholera and typhoid fever [53,54]. However, it has yet to be determined if the high prevalence of the 3435C>T SNP has a heterozygote advantage in these diseases.…”

Section: Discussionmentioning

confidence: 99%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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Section: Discussionmentioning

confidence: 99%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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“…To elucidate whether the CFTR channel, a plasma membrane Cl Ϫ channel, is involved in fluid accumulation caused by hemolysin, the effects of H-89, a cAMP-dependent protein kinase A (PKA) inhibitor (7,27), and glibenclamide, a selective CFTR inhibitor (34,35), were examined. For the control experiment, CT, which causes diarrhea through the activation of CFTR (18,23), was used. H-89 and glibenclamide dose-dependently inhibited the fluid accumulation induced by hemolysin and CT (Fig.…”

Section: Resultsmentioning

confidence: 99%

Fluid Secretion Caused by Aerolysin-Like Hemolysin of Aeromonas sobria in the Intestines Is Due to Stimulation of Production of Prostaglandin E ₂ via Cyclooxygenase 2 by Intestinal Cells

et al. 2008

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To clarify the mechanisms of diarrheal disease induced by Aeromonas sobria, we examined whether prostaglandin E 2 (PGE 2 ) was involved in the intestinal secretory action of A. sobria hemolysin by use of a mouse intestinal loop model. The amount of PGE 2 in jejunal fluid and the fluid accumulation ratio were directly related to the dose of hemolysin. The increase over time in the level of PGE 2 was similar to that of the accumulated fluid. In addition, hemolysin-induced fluid secretion and PGE 2 synthesis were inhibited by the selective cyclooxygenase 2 (COX-2) inhibitor NS-398 but not the COX-1 inhibitor SC-560. Western blot analysis revealed that hemolysin increased the COX-2 protein levels but reduced the COX-1 protein levels in mouse intestinal mucosa in vivo. These results suggest that PGE 2 functions as an important mediator of diarrhea caused by hemolysin and that PGE 2 is produced primarily through a COX-2-dependent mechanism. Subsequently, we examined the relationship between PGE 2 , cyclic AMP (cAMP), and cystic fibrosis transmembrane conductance regulator (CFTR) Cl ؊ channels in mouse intestinal mucosa exposed to hemolysin. Hemolysin increased the levels of cAMP in the intestinal mucosa. NS-398 inhibited the increase in cAMP production, but SC-560 did not. In addition, H-89, a cAMP-dependent protein kinase A (PKA) inhibitor, and glibenclamide, a CFTR inhibitor, inhibited fluid accumulation. Taken together, these results indicate that hemolysin activates PGE 2 production via COX-2 and that PGE 2 stimulates cAMP production. cAMP then activates PKA, which in turn stimulates CFTR Cl ؊ channels and finally leads to fluid accumulation in the intestines.

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“…This can result in potentially lethal chloridesecretory diarrhoea. Cl − secretion in response to CT was shown to be proportional to amounts of CFTR protein in cftr null mice (Gabriel et al 1994). Heterozygous mice secreted 50% of the normal fluid and chloride ions in response to CT.…”

Section: Theories Of Heterozygote Advantagementioning

confidence: 99%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

299

215

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SummaryCystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.

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Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model

Cited by 445 publications

References 28 publications

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

Fluid Secretion Caused by Aerolysin-Like Hemolysin of Aeromonas sobria in the Intestines Is Due to Stimulation of Production of Prostaglandin E ₂ via Cyclooxygenase 2 by Intestinal Cells

The Phenotypic Consequences of CFTR Mutations

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Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model

Cited by 445 publications

References 28 publications

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

Fluid Secretion Caused by Aerolysin-Like Hemolysin of Aeromonas sobria in the Intestines Is Due to Stimulation of Production of Prostaglandin E 2 via Cyclooxygenase 2 by Intestinal Cells

The Phenotypic Consequences of CFTR Mutations

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Fluid Secretion Caused by Aerolysin-Like Hemolysin of Aeromonas sobria in the Intestines Is Due to Stimulation of Production of Prostaglandin E ₂ via Cyclooxygenase 2 by Intestinal Cells