Genomic structure of the human congenital chloride diarrhea (CLD) gene

Haila, Siru; Höglund, Pia; Scherer, Stephen W.; Lee, J R; Kristo, Paula; Coyle, Beth; Trembath, Richard C.; Holmberg, Christer; Chapelle, Albert de la; Kere, Juha

doi:10.1016/s0378-1119(98)00261-3

Cited by 31 publications

(22 citation statements)

References 21 publications

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“…Sequence analysis confirmed that the isolated clone contained 3765 bp of the 5Ј regulatory region of DRA gene identical to a previously published sequence (24). Although genomic structure of DRA has been previously established, the identity of its transcription initiation site remains uncertain (24). We therefore identified the DRA transcription initiation site by primer extension analysis utilizing total RNA isolated from normal human colon and from human intestinal Caco-2 cells.…”

Section: Cloning Of Dra Promoter and Identification Of Transcription supporting

confidence: 76%

Molecular cloning and promoter analysis of downregulated in adenoma (DRA)

Alrefai¹,

Wen²,

Jiang³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Downregulated in adenoma (DRA), also referred to as SLC26A3, is an intestinal anion transporter essential for intestinal chloride absorption. Mutations in DRA result in congenital chloride diarrhea. DRA expression has been shown to be induced by differentiation and to be modulated by cytokines. However, mechanisms of DRA gene transcription and its tissue-specific targeting have not yet been investigated. In this study, we cloned a 3,765-bp promoter fragment of human DRA gene and characterized its activity in human colonic LS174T and Caco-2 human colon cell lines. Primer extension identified a single transcriptional initiation site that was identical in both colon cancer cell lines and normal colon. Although hepatic nuclear factor HNF-4 is involved in the basal activity of DRA promoter, sodium butyrate induces its activity in LS174T cells via the binding of Yin Yang 1 (YY1) and GATA transcription factors to their respective cis-elements in promoter region. We also demonstrated a reduction in DRA promoter activity in Caco-2 cells by IFN-gamma, suggesting that regulation of DRA promoter by IFN-gamma may contribute to the pathophysiology of intestinal inflammation. Furthermore, we showed that the DRA promoter fragment is sufficient to drive human growth hormone transgene expression specifically in villus epithelial cells of the small intestine and in differentiated upper crypt and surface epithelial cells of the colon. Our studies provide evidence for the involvement of HNF-4, YY1, and GATA transcription factors in DRA expression in intestinal differentiated epithelial cells.

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Section: Cloning Of Dra Promoter and Identification Of Transcription supporting

confidence: 76%

Molecular cloning and promoter analysis of downregulated in adenoma (DRA)

Alrefai¹,

Wen²,

Jiang³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Its gene size (,6 kb) is fairly small in relation to its cDNA length (3.8 kb) due to the presence of only three small introns, with the first being an optional intron only occurring in some mRNA transcripts. The genomic structure of Sat1 differs considerably from that of other SO 4 22 or Cl 2 transporters, including Nas1 {15 exons, spanning ,75 kb; (Beck and Markovich, 2000)}, CLD {21 exons spanning ,39 kb; (Haila et al, 1998)} and PDS {21 exons spanning ,59 kb; (Everett et al, 1997)}. The human SAT1 gene was recently sequenced (contig RP11-460I19 in NCBI human genome database; Accession No.…”

Section: Murine Sulfate Anion Transporter Genementioning

confidence: 99%

The Mouse Sulfate Anion Transporter GeneSat1(Slc26a1): Cloning, Tissue Distribution, Gene Structure, Functional Characterization, and Transcriptional Regulation Thyroid Hormone

Lee

Beck

Markovich

2003

DNA and Cell Biology

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Sulfate (SO(4)(2-)) is required for bone/cartilage formation and cellular metabolism. sat-1 is a SO(4)(2-) anion transporter expressed on basolateral membranes of renal proximal tubules, and is suggested to play an important role in maintaining SO(4)(2-) homeostasis. As a first step towards studying its tissue-specific expression, hormonal regulation, and in preparation for the generation of knockout mice, we have cloned and characterized the mouse sat-1 cDNA (msat-1), gene (sat1; Slc26a1) and promoter region. msat-1 encodes a 704 amino acid protein (75.4 kDa) with 12 putative transmembrane domains that induce SO(4)(2-) (also oxalate and chloride) transport in Xenopus oocytes. msat-1 mRNA was expressed in kidney, liver, cecum, calvaria, brain, heart, and skeletal muscle. Two distinct transcripts were expressed in kidney and liver due to alternative utilization of the first intron, corresponding to an internal portion of the 5'-untranslated region. The Sat1 gene (~6 kb) consists of 4 exons. Its promoter is ~52% G + C rich and contains a number of well-characterized cis-acting elements, including sequences resembling hormone responsive elements T(3)REs and VDREs. We demonstrate that Sat1 promoter driven basal transcription in OK cells was stimulated by tri-iodothyronine. Site-directed mutagenesis identified an imperfect T(3)RE at -454-bp in the Sat1 promoter to be responsible for this activity. This study represents the first characterization of the structure and regulation of the Sat1 gene encoding a SO(4)(2-)/chloride/oxalate anion transporter.

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“…Furthermore, expression of the mouse DRA orthologue in human embryonic kidney HEK293 cells, conferred sodium-independent electroneutral Cl -/HCO 3 -exchange activity [45]. The human DRA gene (SLC26A3) was mapped to chromosome 7q22-31.1 [46] and contains 21 exons spanning 39 kb [47]. DRA mRNA was detected in eccrine sweat glands and seminal vesicles [48], and at the mucosal epithelium of the intestinal tract (duodenum, ileum, cecum and distal colon), but not in the esophagus or stomach [43].…”

Section: Slc26a2 Mutations In Chondrodysplasiasmentioning

confidence: 99%

Pathogenetics of the Human SLC26 Transporters

Dawson¹,

Markovich

2005

CMC

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Over the past decade, 11 human genes belonging to the solute linked carrier (SLC) 26 family of transporters, have been identified. The SLC26 proteins, which include SAT-1, DTDST, DRA/CLD, pendrin, prestin, PAT-1/CFEX and Tat-1, are structurally related and have been shown to transport one or more of the following substrates: sulfate, chloride, bicarbonate, iodide, oxalate, formate, hydroxyl or fructose. Special interest has focused on four members of the SLC26 family that are associated with distinct recessive diseases: (i) Mutations in SLC26A2 lead to four different chondrodysplasias (diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB and multiple epiphyseal dysplasia); (ii) SLC26A3 is associated with congenital chloride diarrhea; (iii) SLC26A4 is associated with Pendred syndrome and non-syndromic deafness, DFNB4; and (iv) SLC26A5 is defective in non-syndromic hearing impairment. This review article summarizes current information on the pathophysiological consequences of mutations in the human SLC26A2 to A5 genes.

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Genomic structure of the human congenital chloride diarrhea (CLD) gene

Cited by 31 publications

References 21 publications

Molecular cloning and promoter analysis of downregulated in adenoma (DRA)

Molecular cloning and promoter analysis of downregulated in adenoma (DRA)

The Mouse Sulfate Anion Transporter GeneSat1(Slc26a1): Cloning, Tissue Distribution, Gene Structure, Functional Characterization, and Transcriptional Regulation Thyroid Hormone

Pathogenetics of the Human SLC26 Transporters

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