Loss of consciousness and hypokalemia in an elderly man with a mutation of the thiazide-sensitive Na-Cl cotransporter gene.
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An 80-year-old man was referred to our department for evaluation of repetitive loss of consciousness and faintness with hypokalemia. He had relatively low blood pressure, hypomagnesemia, hypocalciuria and chondrocalcinosis in the knee, clinically suggesting Gitelman's syndrome. A renal clearance study could not be carried out due to the patient's age and complications of the heart. Sequence analysis of the gene of thiazide-sensitive Na-Cl cotransporter (TSC) showed a heterozygous missense mutation from C to T at 1712 base pairs from the translation start site, with resultant changes in codon 569 from alanine to valine (A569V). Treatment with oral administration of potassium chloride improved all the symptoms. Although Gitelman's syndrome has been considered to be autosomal recessive, cases of only heterozygous mutation detected have recently been reported. Therefore, the mutation found in this patient may be responsible for Gitelman's syndrome. (+info)
Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome.
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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. (+info)
TRP channels in kidney disease.
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Mammalian TRP channel proteins form six-transmembrane cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cell functions and are considered to play an important role in the pathophysiology of many diseases. Many TRPs are expressed in kidney along different parts of the nephron and growing evidence suggest that these channels are involved in hereditary, as well as acquired kidney disorders. TRPC6, TRPM6, and TRPP2 have been implicated in hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively. In addition, the highly Ca(2+)-selective channel, TRPV5, contributes to several acquired mineral (dys)regulation, such as diabetes mellitus (DM), acid-base disorders, diuretics, immunosuppressant agents, and vitamin D analogues-associated Ca(2+) imbalance whereas TRPV4 may function as an osmoreceptor in kidney and participate in the regulation of sodium and water balance. This review presents an overview of the current knowledge concerning the distribution of TRP channels in kidney and their possible roles in renal physiology and kidney diseases. (+info)
A thiazide test for the diagnosis of renal tubular hypokalemic disorders.
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Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children-adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with "pseudo-BS" from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping. (+info)
Disorders of renal magnesium handling explain renal magnesium transport.
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Magnesium is essential for bone stability, neuronal excitability, muscular relaxation and many other metabolic functions. Despite its fundamental biological importance, mechanisms controlling systemic magnesium homeostasis are only partially understood. The kidney plays a central role in maintaining magnesium balance as evident from several rare inherited disorders of renal magnesium transport. Recent studies shed new light on molecular mechanisms of renal magnesium handling and its control. Mutations in the claudin 16 (paracellin) paracellular protein in the thick ascending limb (TAL) of Henle's loop and in the transient receptor potential cation channel, subfamily 6, member 6 (TRPM6) magnesium channel expressed in distal tubules found in patients with renal magnesium wasting and hypomagnesemia underscore the importance of these transport proteins. A study by Hou et al (J Biol Chem 2007; 282: 17114-22) demonstrates a pathomechanism for claudin 16 mutations that gives interesting insights into the function of the TAL. Moreover, Groenestege and colleagues report (J Clin Invest 2007; 117: 2260-7) the identification of the epidermal growth factor (EGF) as a hormonal regulator of TRPM6 activity, and thereby explain how mutations in EGF can cause familial hypomagnesemia. Interestingly, cetuximab, a drug used in treatment of certain cancers, acts an inhibitor of the EGF receptor and causes hypomagnesemia which may be due to the inhibition of EGF signaling. (+info)
Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure.
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Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1,000,000, in Sweden, suggesting that approximately 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies. (+info)
Absence of vascular remodelling in a high angiotensin-II state (Bartter's and Gitelman's syndromes): implications for angiotensin II signalling pathways.
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Case-control study of the role of the Gitelman's syndrome gene in essential hypertension.
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BACKGROUND: Gitelman's syndrome is an inherited tubular disorder characterized by sodium wasting, low blood pressure, secondary hyperaldosteronism, metabolic alkalosis, hypokalemia, hypomagnesemia of renal origin, and hypocalciuria. The majority of patients with this syndrome carry inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive Na (+)-Cl (-) cotransporter (NCC) located in the distal convoluted tubule, which is involved in renal sodium reabsorption. This suggests that the SLC12A3 gene is involved in mediation of blood pressure levels. The aim of the present study was to investigate relationships between single nucleotide polymorphisms (SNPs) in the human SLC12A3 gene and essential hypertension (EH) in Japanese. METHOD: We selected 3 SNPs in the human SLC12A3 gene (T180K, A569V, L849H), and performed a case-control study of 315 EH patients and 305 normotensive (NT) individuals. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNPs between the EH and NT groups. CONCLUSION: We conclude that the causal gene of Gitelman's syndrome is not involved in determining blood pressure levels. (+info)