The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Kere, Juha; Sistonen, P; Holmberg, Christer; Chapelle, Albert de la

doi:10.1073/pnas.90.22.10686

Cited by 37 publications

(10 citation statements)

References 28 publications

(25 reference statements)

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“…DRA gene consists of 21 exons and is localized to chromosome 7q22-q31.1 [104]. The DRA cDNA encodes for a protein of 764 amino acids with a predicted molecular weight of 85 kDa [104].…”

Section: Cl−/hco3− Exchangersmentioning

confidence: 99%

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Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters

et al. 2011

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The epithelial apical membrane Na+/H+ exchangers (NHE2, NHE3) and Cl−/HCO3− exchangers (DRA and PAT-1) are key luminal membrane transporters involved in electroneutral NaCl absorption in the mammalian intestine. During the past decade, there has been a surge of studies focusing on short-term regulation of these electrolyte transporters particularly for NHE3 regulation. However, the long-term regulation of the electrolyte transporters involving transcriptional mechanisms and transcription factors that govern their basal regulation or dysregulation in diseased states has only now started to unfold with the cloning and characterization of their gene promoters. This review updates the readers with a detailed analysis of the core promoters of NHE2, NHE3, DRA and PAT-1 and outlines the transcription factors involved in their basal regulation as well as in response to both physiological (butyrate, protein kinases, probiotics) and pathophysioloical (cytokines and high levels of serotonin) stimuli. The available information on the transcriptional regulation of the recently identified NHE8 isoform is also highlighted. This review, therefore, bridges a gap in our knowledge of the transcriptional mechanisms underlying the alterations in the gene expression of intestinal epithelial luminal membrane Na+ and Cl− transporters involved in electroneutral NaCl absorption. An understanding of the mechanisms of modulation of gene expression of these transporters is important for a better assessment of the pathophysiology of diarrhea associated with inflammatory and infectious diseases and may aid in designing better management protocols.

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“…DRA gene consists of 21 exons and is localized to chromosome 7q22-q31.1 [104]. The DRA cDNA encodes for a protein of 764 amino acids with a predicted molecular weight of 85 kDa [104].…”

Section: Cl−/hco3− Exchangersmentioning

confidence: 99%

“…The DRA cDNA encodes for a protein of 764 amino acids with a predicted molecular weight of 85 kDa [104]. …”

Section: Cl−/hco3− Exchangersmentioning

confidence: 99%

Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters

et al. 2011

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“…Genealogical studies of Finnish families with CLD indicated autosomal recessive inheritance [Norio et al, 1971]. Subsequent genetic, molecular, and population genetic approaches in the Finnish founder population [Norio, 1971;de la Chapelle, 1993] allowed mapping of the locus for CLD to chromosome 7q31 [Kere et al, 1993]. The localization was refined to a 0.37 cM region by studying linkage disequilibrium in Finnish CLD associated haplotypes [Höglund et al, 1995].…”

Section: Molecular Genetics Of Cldmentioning

confidence: 99%

SLC26A3 mutations in congenital chloride diarrhea

et al. 2002

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Congenital chloride diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte absorption. It is characterized by persistent secretory diarrhea resulting in polyhydramnios and prematurity prenatally, and dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive immediately after birth. CLD is caused by mutations in the solute carrier family 26, member 3 gene (SLC26A3, alias CLD or DRA), which encodes a Na+-independent Cl-/HCO3- (or OH-) exchanger. SLC26A3 is a member of the SLC26 sulfate permease/anion transporter family and it is expressed mainly in the apical brush border of intestinal epithelium. The only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. A wide variety of different mutations in the SLC26A3 gene have been associated with CLD with no apparent evidence of phenotype-genotype correlation. The clinical course of CLD, however, is variable and may rather depend on environmental factors and compensatory mechanisms than mutations. In this report, we present a summary of all published and two novel SLC26A3 mutations and polymorphisms, and review them in the context of their functional consequences and clinical implications.

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“…The locus was assigned by linkage analysis to a 10-cM region, and every CLD chromosome in Finland occurred on the same, extended haplotype, suggesting a single founding mutation (␣ ϭ 1) (27,77). The critical region was narrowed to approximately 0.37 cM by linkage disequilibrium analysis, and this region contained two previously cloned genes, one of which, down-regulated in adenoma (DRA), turned out to be responsible for the disease (28).…”

Section: Chloride Diarrhea (Cld)mentioning

confidence: 99%

Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

Chapelle

Wright²

1998

Proc. Natl. Acad. Sci. U.S.A.

201

105

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Linkage disequilibrium analysis can provide high resolution in the mapping of disease genes because it incorporates information on recombinations that have occurred during the entire period from the mutational event to the present. A circumstance particularly favorable for high-resolution mapping is when a single founding mutation segregates in an isolated population. We review here the population structure of Finland in which a small founder population some 100 generations ago has expanded into 5.1 million people today. Among the 30-odd autosomal recessive disorders that are more prevalent in Finland than elsewhere, several appear to have segregated for this entire period in the ''panmictic'' southern Finnish population. Linkage disequilibrium analysis has allowed precise mapping and determination of genetic distances at the 0.1-cM level in several of these disorders. Estimates of genetic distance have proven accurate, but previous calculations of the confidence intervals were too small because sampling variation was ignored. In the north and east of Finland the population can be viewed as having been ''founded'' only after 1500. Disease mutations that have undergone such a founding bottleneck only 20 or so generations ago exhibit linkage disequilibrium and haplotype sharing over long genetic distances (5-15 cM). These features have been successfully exploited in the mapping and cloning of many genes. We review the statistical issues of fine mapping by linkage disequilibrium and suggest that improved methodologies may be necessary to map diseases of complex etiology that may have arisen from multiple founding mutations.

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The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Abstract: Congenital chloride diarrhea (CLD) is char-

Cited by 37 publications

References 28 publications

Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters

Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters

SLC26A3 mutations in congenital chloride diarrhea

Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

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The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Abstract: Congenital chloride diarrhea (CLD) is char-

Cited by 37 publications

References 28 publications

Transcriptional regulation of the intestinal luminal Na+and Cl−transporters

Transcriptional regulation of the intestinal luminal Na+and Cl−transporters

SLC26A3 mutations in congenital chloride diarrhea

Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

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Product

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Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters

Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters