Genetic Variants of Thiazide-Sensitive NaCl-Cotransporter in Gitelman’s Syndrome and Primary Hypertension

IntroductionThiazide diuretics (TZDs) have been most widely used as a first line antihypertensive drug (1,2). Recently, the ALLHAT study confirmed the usefulness of TZDs for the reduction of blood pressure (BP) and cardiovascular diseases in comparison with newer antihypertensive drugs, including Ca channel blockers (CCBs) such as amlodipine and angiotensin converting enzyme inhibitors (ACEIs) such as lisinopril in about 40,000 hypertensive patients with high risk factors (3). TZDs are not only effective as a monotherapy for hypertension, but are also very useful for combination therapy with other antihypertensive drugs (4). Moreover, the use of a TZD as a drug therapy for hypertension, which is a chronic and lifelong disease, would be very good from the viewpoint of the cost of drugs, because TZDs are the cheapest of all antihypertensive drugs. However, the response of BP to TZDs differs among individuals, and TZDs often induce side effects, such as hypokalemia and lipid, glucose and uric acid metabolism abnormalities (4). Therefore, it would be useful to determine the individual sensitivity to a TZD before prescribing it.Regarding previous findings about gene polymorphisms that influence TZD-sensitivity, Turner et al. (5) reported that the β3-subunit of the G protein (GNB3) C825T polymorphism was related to the antihypertensive effect of a TZD in Caucasian and African-American subjects with essential hypertension (EHT). Glorioso et al. (6) also demonstrated that the α-adducin (ADD1) Gly460Trp polymorphism is the gene conferring susceptibility to the antihypertensive effect of TZDs in Italian hypertensives. This ADD1 Gly460Trp polymorphism was also suggested to confer susceptibility to saltsensitivity in Caucasians and Asians with EHT (7).Mutations of causative genes have recently been detected in several monogenic electrolyte disorders, such as mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) gene for Gitelman syndrome (8, 9), the WNK1 and 4 genes for Gordon syndrome (pseudohypoaldosteronism type II) (10) and the mineral corticoid receptor (MLR) for pseudohypoaldosteronism type I (PHA I) (11). TZDs are commonly effective for treating Gitelman syndrome and Gordon syndrome. We also focused on the Na /Ca 2 exchanger gene (NCX1), because its impairment was recently reported in mesangial cells from salt-sensitive hypertensive rats (12). TZDs are known to be effective for salt-sensitive hypertension. It is also known that the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are activated in response to changes in circulating blood volume after TZD administration. Therefore, it is expected that gene polymorphisms related to the RAAS and SNS might be involved in the antihypertensive effect of TZDs. The present study investigated the gene polymorphism influencing the TZD-sensitivity by analyzing mainly single nucleotide polymorphisms (SNPs) of several water-electrolyte-related genes, including GN3B, ADD1, TSC, MLR, NCX1, WNK1, WNK4 and RAAS-and SNS-related genes, to antici...

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“…(30). It has recently been reported that TSC might interact with WNK4, which is one of the causative genes of Gordon syndrome (31,32).…”

Section: Discussionmentioning

confidence: 99%

The Thiazide-Sensitive Na+-Cl- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

Matayoshi¹,

Kamide²,

Takiuchi³

et al. 2004

Hypertens Res

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“…The prevalence of heterozygotes is approximately 1% in European populations (1), making it the most frequent inherited tubulopathy. The disease is due to loss of function mutations in the SLC12A3 gene (16q13) that codes for the thiazide-sensitive NaCl co-transporter (NCC) (2)(3)(4)(5)(6)(7)(8)(9)(10).…”

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confidence: 99%

Transcriptional and Functional Analyses of SLC12A3 Mutations

Riveira-Muñoz¹,

Chang²,

Godefroid³

et al. 2007

Journal of the American Society of Nephrology

143

125

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Gitelman syndrome (GS) is a recessive salt-losing tubulopathy that is caused by mutations in the SLC12A3 gene that encodes the sodium-chloride co-transporter (NCC). GS is characterized by significant inter-and intrafamilial phenotype variability, with early onset and/or severe clinical manifestations in some patients. No correlations between the disease variability and the position/nature of SLC12A3 mutations have been investigated thus far. 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. Twenty-six SLC12A3 mutations were identified in 25 patients with GS, including eight novel (detection rate 80%). Transcript analysis demonstrated that splicing mutations of SLC12A3 lead to frameshifted mRNA subject to degradation by nonsense-mediated decay. Heterologous expression documented a novel class of NCC mutants with defective intrinsic transport activity. A subgroup of patients presented with early onset, growth retardation, and/or detrimental manifestations, confirming the potential severity of GS. The mutations that were associated with a severe presentation were the combination at least for one allele of a missplicing resulting in a truncated transcript that was downregulated by nonsense-mediated decay or a nonfunctional, cell surface-absent mutant. The most recurrent mutation on the second allele was a newly described NCC mutant that affected the functional properties of the co-transporter. These data suggest that the nature/position of SLC12A3 mutation, combined with male gender, is a determinant factor in the severity of GS and provide new insights in the underlying pathogenic mechanisms of the disease.

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“…TSC is a target of the diuretic effect of thiazides and is an established antihypertensive drug in the management of uncomplicated hypertension. Mutations in the human TSC (hTSC) gene affect blood pressure regulation, as seen in Gitelman's syndrome (Melander et al, 2000), which is a disease characterized by sodium wasting and low blood pressure. These characteristics validated the TSC gene as a logical candidate gene for hypertension susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, genetic investigations have revealed several genetic variants that are candidates in the pathogenesis of hypertension (Johnson et al, 2011;Hasi et al, 2011;Fu et al, 2011). Current studies suggest that the thiazide-sensitive Na-Cl cotransporter (TSC) gene plays an important role on the risk of essential hypertension in diverse ethnic groups (Melander et al, 2000;Song et al, 2001;Glorioso et al, 2001;Matsuo et al, 2004;Zhan et al, 2007;Wang et al, 2008). The TSC gene is located on chromosome 16q13, consisting of 26 exons that encode 1021-amino acid residues (Plotkin et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…The TSC gene is located on chromosome 16q13, consisting of 26 exons that encode 1021-amino acid residues (Plotkin et al, 1996). Among the SNPs of the TSC gene, Arg904Gln is at amino acid position 904 of the thiazide-sensitive NaCl-cotransporter, the G→A mutation in exon 23 of the TSC gene (G2736A), which leads to a replacement of Arg by Gln (Melander et al, 2000). Compared with other SNPs of the TSC gene, such as Gly264Ala and C1420T (Melander et al, 2000), it is reported more frequently as associated with essential hypertension risk.…”

Section: Introductionmentioning

confidence: 99%

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Lack of an association between TSC gene Arg904Gln polymorphisms and essential hypertension risk based on a meta-analysis

Zhang¹,

Yang²,

Hu³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Although there have been several studies investigating a possible association between essential hypertension and TSC gene Arg904Gln polymorphisms, the results have been inconsistent. We conducted a meta-analysis of four case-control studies (one study in Europe and three studies in Asia), including 1811 essential hypertension cases and 1381 controls. The pooled results showed no significant associations between any of these polymorphisms and essential hypertension (allele Arg vs allele Gln: odds ratio (OR) = 0.94, 95% confidence interval (95%CI) = 0.70-1.27), additive genetic model (Arg/Arg vs Gln/Gln: OR = 0.98, 95%CI = 0.43-2.23), dominant genetic model (Arg/Arg + Arg/Gln vs Gln/ Gln: OR = 0.97, 95%CI = 0.43-2.21), and recessive genetic model (Arg/ Arg vs Arg/Gln + Gln/Gln: OR = 1.03, 95%CI = 0.45-2.35). Based on the results of our meta-analysis, we conclude that the TSC gene Arg904Gln polymorphism is not associated with essential hypertension risk.

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Genetic Variants of Thiazide-Sensitive NaCl-Cotransporter in Gitelman’s Syndrome and Primary Hypertension

Cited by 80 publications

References 23 publications

The Thiazide-Sensitive Na+-Cl- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

The Thiazide-Sensitive Na+-Cl- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

Transcriptional and Functional Analyses of SLC12A3 Mutations

Lack of an association between TSC gene Arg904Gln polymorphisms and essential hypertension risk based on a meta-analysis

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