Disease relevance of SLC12A3

• We genotyped 11 common single nucleotide polymorphisms (SNPs) in the SLC12A3 gene in 177 patients with ESRD due to type 2 diabetes and 184 patients with diabetic retinopathy but with no signs of renal involvement [1].
• In contrast, NCCT patients had hypocalciuria, hypomagnesemia, and marked hypokalemia [2].
• We examined the genetic involvement of the TSC gene in essential hypertension in Japanese. DESIGN: Participants were recruited from outpatients of Osaka University Hospital. We investigated 386 hypertensive and 371 normotensive subjects [3].
• Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome [4].
• BACKGROUND: To investigate the genetic cause of inherited hypokalemic metabolic alkalosis associated with Gitelman's syndrome, we searched for mutations in the SLC12A3 gene (thiazide-sensitive NaCl cotransporter) among a set of patients from the Czech Republic and Slovakia [5].

High impact information on SLC12A3

• Our survey of more than 1,200 SNPs indicates that more than 80% of TSC and Washington University candidate SNPs are polymorphic and that approximately 50% of the candidate SNPs from these two sources are common SNPs (with minor allele frequency of > or =20%) in any given population [6].
• Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter ((22)Na-influx reduced 50%, P < 1 x 10(-9), surface expression reduced 75%, P < 1 x 10(-14) in the presence of WNK4) [7].
• PHAII-causing missense mutations, which are remote from the kinase domain, also prevent inhibition of NCCT activity, providing insight into the pathophysiology of the disorder [7].
• To address this possibility, we measured NCCT-mediated Na(+) influx and membrane expression in the presence of wild-type and mutant WNK4 by heterologous expression in Xenopus oocytes [7].
• The Cl(-) dependence of PHAII phenotypes, their sensitivity to thiazide diuretics, and the observation that they constitute a "mirror image" of the phenotypes resulting from loss of function mutations in the thiazide-sensitive Na-Cl cotransporter (NCCT) suggest that PHAII may result from increased NCCT activity due to altered WNK signaling [7].

Chemical compound and disease context of SLC12A3

• In a multicenter, double-blind, randomized, controlled trial, TSC 30% was compared with unfractionated heparin 5000 U/ml for prevention of catheter-related infections, thrombosis, and bleeding complications [8].
• BACKGROUND: The combination of isosulfan blue (Lymphazurin) 1% and 99(m)Tc sulfur colloid (TSC) may improve the feasibility and accuracy of lymphatic mapping for colorectal cancer [9].

Biological context of SLC12A3

• Data base analysis revealed that 135 single nucleotide polymorphisms along the human SLC12A3 gene that encodes the Na+:Cl- cotransporter have been reported [10].
• CONCLUSIONS/INTERPRETATION: The SLC12A3 +78A(+) genotype may have a protective effect against the development and/or progression of diabetic nephropathy in Japanese type 2 diabetic patients [11].
• CONCLUSION: Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect [12].
• In mammals, these proteins are encoded by three distinct but related genes: SLC12A1, SLC12A2, SLC12A3, which are located on different chromosomes [13].
• This case report confirms the feasibility of using readily accessible blood cells to study the expression of the SLC12A3 gene, a procedure that may facilitate further studies of the functional genomics of Gitelman syndrome [14].

Anatomical context of SLC12A3

• OBJECTIVE: The thiazide-sensitive Na-Cl cotransporter (TSC) is located in the distal renal tubules [3].
• In this study, extensive mutational analyses of SLC12A3 were performed in 27 patients with GS, including genomic DNA sequencing, multiplex ligation-dependent probe amplification, cDNA analysis, and quantification of allele-specific transcripts, in parallel with functional analyses in Xenopus laevis oocytes and detailed phenotyping [15].
• This promoter, and all other promoter constructs from SLC12A3, displayed repressor activity in CHO cells [16].
• Protein-DNA interactions between the 182 bp region immediately upstream of the start codon and the nuclear proteins from rat kidney cortex and HeLa cells were examined to further clarify the role of the putative binding sites for SLC12A3 expression [16].
• We sequenced 1959 bp of the 5' flanking region of human SLC12A3, located the area of transcription initiation, and used deletion constructs of the flanking region to determine areas that affect reporter gene expression in two cell lines, MDCT and CHO [16].

Associations of SLC12A3 with chemical compounds

• Polymorphism of the solute carrier family 12 (sodium/chloride transporters) member 3, SLC12A3, gene at exon 23 (+78G/A: Arg913Gln) is associated with elevation of urinary albumin excretion in Japanese patients with type 2 diabetes: a 10-year longitudinal study [11].
• The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule [12].
• RESULTS: All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene [12].
• Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3) [17].
• The homology of the hTSC with rat TSC (rTSC) and rat bumetanide-sensitive sodium-potassium-chloride cotransporter (rBSC) was 86% and 64%, respectively, at the nucleotide level, and 92% and 61%, respectively, at the amino acid level [18].

Regulatory relationships of SLC12A3

• Recent studies have revealed that cell surface expression of TSC is regulated by WNK1 and WNK4 [19].

Other interactions of SLC12A3

• We hypothesized that molecular variations in TSC, WNK1, and WNK4 could lead to an increased morbidity of hypertension [19].
• Two of the genes in this branch ( SLC12A1 and SLC12A3), exhibit kidney-specific expression and function in renal salt reabsorption, whereas the third gene ( SLC12A2) is expressed ubiquitously and plays a key role in epithelial salt secretion and cell volume regulation [20].
• Association of TSC and WNK1 with hypertension was not observed [19].
• No mutations were found in CLDN16 and SLC12A3 either [21].
• These results suggest that the SLC12A3 gene locus is associated with ESRD due to diabetic nephropathy [1].

Analytical, diagnostic and therapeutic context of SLC12A3

• METHODS: Genotypes of TSC polymorphisms (G2736A, C1420T, G816C) were determined by the TaqMan polymerase chain reaction (PCR) method, and statistical significance was examined using JMP 5.0.1J (SAS Institute Inc., Cary, North Carolina, USA) [3].
• The expression pattern of the human Na-Cl thiazide-sensitive cotransporter (hTSC, HGMW-approved symbol SLC12A3) confirms the kidney specificity. hTSC has been mapped to human chromosome 16q13 by fluorescence in situ hybridization [17].
• Sequence analysis of this minimal promoter responsible for most of the SLC12A3 promoter activity revealed a TATA element, two Sp binding sites, a potential E box, and a potential binding site for NF-1/CTF or NY-I/CP-I [16].
• INVESTIGATIONS: Physical examination, urine and blood analyses, chest radiography, electrocardiogram, renal ultrasound, and genetic analysis focusing on the SLC12A3 gene, which encodes the thiazide-sensitive Na/Cl cotransporter [22].
• TSC 30% improves overall patency rates and reduces catheter-related infections and major bleeding episodes for both tunneled and untunneled hemodialysis catheters [8].

References