Positional candidate genes for congenital chloride diarrhea suggested by high-resolution physical mapping in chromosome region 7q31.

Höglund, Pia; Haila, Siru; Scherer, Stephen W.; Tsui, Lap‐Chee; Green, E D; Weissenbach, Jean; Holmberg, Christer; Chapelle, Albert de la; Kere, Juha

doi:10.1101/gr.6.3.202

Cited by 36 publications

(32 citation statements)

References 29 publications

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“…Together with NHE3, the SLC26A3 Cl -/HCO 3 -exchanger (or downregulated in adenoma; DRA), a member of the SLC26 gene family, maintains the absorption of NaCl in the colon. Mutation of this transporter results in congenital chloride-losing diarrhoea [19], moreover, similar conditions develop in SLC26A3-deficient mice [36]. The fact that impaired activities of these transporters were observed in diarrhoea-associated diseases, such as ulcerative colitis and secretory diarrhoea [8,28,50], further underlies the importance of the NHE3 and SLC26A3 in colonic electrolyte and water absorption.…”

Section: Discussionmentioning

confidence: 99%

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Pallagi-Kunstár

Farkas

Maléth

et al. 2014

Pflugers Arch - Eur J Physiol

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Abstract:Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileumresected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl-/HCO3-exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 AbstractBile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na + /H + exchanger (NHE) and Cl -/HCO 3 -exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca 2+ elevation. We also showed that chenodeoxycholate induced Ca 2+ release from the endoplasmic reticulum and extracellular Ca 2+ influx contributing to the Ca 2+ elevation. Importantly, our results suggest that the chenodeoxycholate induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca 2+ elevation.We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca 2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote ...

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Section: Discussionmentioning

confidence: 99%

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Pallagi-Kunstár

Farkas

Maléth

et al. 2014

Pflugers Arch - Eur J Physiol

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“…Among these genes, we focused our attention on Slc26a3, a gene whose mutations are associated to congenital chloride diarrhoea (OMIM 214700). This disease is manifested by enhanced chloride and water loss in stools (Hoglund et al, 1996). The encoded protein is a Cl -/HCO 3 -exchanger driving NaCl absorption.…”

Section: Hnf1 Transcription Factors Control Water Absorptionmentioning

confidence: 99%

Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium

et al. 2010

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SUMMARYThe intestinal epithelium is a complex system characterized by massive and continuous cell renewal and differentiation. In this context, cell-type-specific transcription factors are thought to play a crucial role by modulating specific transcription networks and signalling pathways. Hnf1a and b are closely related atypical homeoprotein transcription factors expressed in several epithelia, including the gut. With the use of a conditional inactivation system, we generated mice in which Hnf1b is specifically inactivated in the intestinal epithelium on a wild-type or Hnf1a -/-genetic background. Whereas the inactivation of Hnf1a or Hnf1b alone did not lead to any major intestinal dysfunction, the concomitant inactivation of both genes resulted in a lethal phenotype. Double-mutant animals had defective differentiation and cell fate commitment. The expression levels of markers of all the differentiated cell types, both enterocytes and secretory cells, were affected. In addition, the number of goblet cells was increased, whereas mature Paneth cells were missing. At the molecular level, we show that Hnf1a and b act upstream of the Notch pathway controlling directly the expression of two crucial components: Jag1 and Atoh1. We demonstrate that the double-mutant mice present with a defect in intestinal water absorption and that Hnf1a and b directly control the expression of Slc26a3, a gene whose mutations are associated with chloride diarrhoea in human patients. Our study identifies new direct target genes of the Hnf1 transcription factors and shows that they play crucial roles in both defining cell fate and controlling terminal functions in the gut epithelium. KEY WORDS: Gut epithelium, Hnf1, Commitment, Differentiation, MouseHepatocyte nuclear factor 1a and b control terminal differentiation and cell fate commitment in the gut epithelium

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“…Pedigree data was obtained from the Icelandic Genetic Council at the University Hospital of Iceland and verification of cancer diagnoses from the Department of Pathology, University Hospital of Iceland, and at the Icelandic Cancer Registry. Five of the families (2F, 4, 5A/ B, 6, and 7A/C) were large high risk families and 13 were pairs of sisters (2,10,13,15,16,21,23,24,32,51,57,59, and 67) diagnosed with breast cancer at the age of 60 years or younger. The Finnish 999del5 families were ascertained by four different research groups at the Helsinki, Tampere and Oulu University Hospitals by mutation screening of breast and breast-ovarian cancer families.…”

Section: Kindredsmentioning

confidence: 99%

“…The number of generations (g) since the common ancestors of the families studied, denoted as the time since the spreading of the mutation, was estimated using the LuriaDelbru Èck calculation 12,22,23 of p excess =a(17y) g , where a=1 (all chromosomes carry the same mutation), and y refers to the recombination fraction between the mutation and marker locus. The definition of p excess was based on the haplotype reconstructions (Figures 1 and 3).…”

Section: Genotypingmentioning

confidence: 99%

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families

Barkardóttir¹,

Sarantaus

Arason

et al. 2001

Eur J Hum Genet

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The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340 ± 1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct *6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140 ± 300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion. European Journal of Human Genetics (2001) 9, 773 ± 779.

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Positional candidate genes for congenital chloride diarrhea suggested by high-resolution physical mapping in chromosome region 7q31.

Cited by 36 publications

References 29 publications

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families

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