Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes

Müller, Thomas; Wijmenga, Cisca; Phillips, Alan D.; Janecke, Andreas R.; Houwen, Roderick H. J.; Fischer, Hartmut; Ellemunter, Helmut; Frühwirth, Martin; Offner, Felix; Hofer, Sabine E.; Müller, Wendt; Booth, I W; Heinz‐Erian, Peter

doi:10.1053/gast.2000.20514

Cited by 75 publications

(58 citation statements)

References 23 publications

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“…It is likely that NHE3 and NHE8 perform these compensatory roles, at least under some circumstances [6,51,69]. Perhaps not surprising, given the relatively benign phenotype for NHE2 KO mice, there is no known human disease ascribed to defects in this transporter [110].…”

Section: Slc9a2 -Nhe2mentioning

confidence: 99%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

141

122

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The SLC9 gene family encodes Na + /H + exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

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Section: Slc9a2 -Nhe2mentioning

confidence: 99%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

141

122

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“…However, in a contrasting phenotype, mice lacking the NHE3 Na ϩ /H ϩ exchanger exhibit severe diarrhea and have increased luminal fluid throughout the intestinal tract (51). Additionally, toxin B of Clostridium difficile, which induces diarrhea in humans, acts by inhibiting NHE3 activity (25), and there have been reports of congenital Na ϩ -wasting diarrhea that appear to be due to impaired Na ϩ /H ϩ exchange (41). Loss of NHE3 has been shown to cause a severe reduction in Na ϩ absorption in the intestine (22), with partial compensation occurring in the colon via upregulation of both the epithelial Na ϩ channel and the colonic H ϩ -K ϩ -ATPase (51), which is needed for maximum Na ϩ channel activity (55).…”

mentioning

confidence: 99%

Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

Bradford¹,

Sartor²,

Gawenis³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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In cystic fibrosis, impaired secretion resulting from loss of activity of the cystic fibrosis transmembrane conductance regulator (CFTR) causes dehydration of intestinal contents and life-threatening obstructions. Conversely, impaired absorption resulting from loss of the NHE3 Na+/H+ exchanger causes increased fluidity of the intestinal contents and diarrhea. To test the hypothesis that reduced NHE3-mediated absorption could increase survival and prevent some of the intestinal pathologies of cystic fibrosis, Cftr/Nhe3 double heterozygous mice were mated and their offspring analyzed. Cftr-null mice lacking one or both copies of the NHE3 gene exhibited increased fluidity of their intestinal contents, which prevented the formation of obstructions and increased survival. Goblet cell hyperplasia was eliminated, but not the accumulation of Paneth cell granules or increased cell proliferation in the crypts. Microarray analysis of small intestine RNA from Cftr-null, NHE3-null, and double-null mice all revealed downregulation of genes involved in xenobiotic metabolism, including a cohort of genes involved in glutathione metabolism. Expression of energy metabolism genes was altered, but there were no changes in genes involved in inflammation. Total intracellular glutathione was increased in the jejunum of all of the mutants and the ratio of reduced to oxidized glutathione was reduced in Cftr-null mutants, indicating that CFTR deficiency affects intestinal glutathione metabolism. The data establish a major role for NHE3 in regulating the fluidity of the intestinal contents and show that reduced NHE3-mediated absorption reverses some of the intestinal pathologies of cystic fibrosis, thus suggesting that it may serve as a potential therapeutic target.

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“…Several compensatory mechanisms have been shown to modify the mouse phenotype (34,40), and no human cases of sodium diarrhea have been associated with mutations in the six Na ϩ /H ϩ exchangers cloned to date (36).…”

mentioning

confidence: 99%

Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis

Lohi

Mäkelä

Pulkkinen

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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In inflamed colonic mucosa, the equilibrium between absorptive and secretory functions for electrolyte and salt transport is disturbed. We compared the expression of three major mediators of the intestinal salt transport between healthy and inflamed colonic mucosa to understand the pathophysiology of diarrhea in inflammatory bowel disease. Expression levels of the cystic fibrosis transmembrane regulator (CFTR) (Cl− channel), SLC26A3 (Cl−/HCO[Formula: see text] exchanger) and SLC9A3 (Na+/H+ exchanger) mRNAs were measured by real-time quantitative RT-PCR in peroperative colonic samples from controls ( n = 4) and patients with ulcerative colitis ( n = 10). Several samples were obtained from each individual. Tissue samples were divided into three subgroups according to their histological degree of inflammation. Expression of CFTR and SLC26A3 proteins were determined by immunohistochemistry and Western blotting from the same samples, respectively. Increased expression of CFTR mRNA was observed in all three groups of affected tissue samples, most pronounced in mildly inflamed colonic mucosa (5-fold increase in expression; P < 0.001). The expression of the CFTR protein was detected from health and inflamed colon tissue. Although the expression of the SLC26A3 mRNA was significantly decreased in severe ulcerative colitis ( P< 0.05), the SLC26A3 protein levels remained unchanged in all groups. The expression of SLC9A3 mRNA was significantly changed between the mild and severe groups. Intestinal inflammation modulates the expression of three major mediators of intestinal salt transport and may contribute to diarrhea in ulcerative colitis both by increasing transepithelial Cl− secretion and by inhibiting the epithelial NaCl absorption.

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Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes

Cited by 75 publications

References 23 publications

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis

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Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes

Cited by 75 publications

References 23 publications

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis

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Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice