Novel mutations in the<i>SLC12A3</i>gene causing Gitelman's syndrome in Swedes

Fava, Cristiano; Montagnana, Martina; Rosberg, L.; Burri, Philippe; Jönsson, Anders; Wanby, Pär; Wahrenberg, Hans; Hulthén, U L; Aurell, Mattias; Guidi, Gian Cesare; Melander, Olle

doi:10.1080/10425170701400456

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…3B ). Of note, mutations of NCC (I150M, V153M, I154F, and P349L) can cause Gitelman syndrome, suggesting the vital role of these residues in the transport activity of NCC (table S2) ( 2 , 12 , 37 ).…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of the human sodium-chloride cotransporter NCC

et al. 2022

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The sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. Here, we present the full-length structure of human NCC, with 2.9 Å for the transmembrane domain and 3.8 Å for the carboxyl-terminal domain. NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na2 site are observed in our structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na1 and Cl1 and might also mediate the coordination of Na2 through a Ser residue. Putative observed water molecules are indicated to participate in the coordination of ions and TM coupling. Together with transport activity assays, our structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC.

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Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of the human sodium-chloride cotransporter NCC

et al. 2022

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“…It should be noted, however, that the homozygous or compound heterozygous patients tended to be slightly younger, which is not surprising for an inherited disease, with a tendency toward a lower blood pressure. Indeed, a significantly lower blood pressure in heterozygous patients has already been shown, but this was in population and case-control studies (12)(13)(14). GS is usually described as a clinical model of hypotension or normotension (15,16).…”

Section: Discussionmentioning

confidence: 99%

Phenotype–genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome

Balavoine

Bataille

Vanhille

et al. 2011

European Journal of Endocrinology

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Introduction: Gitelman syndrome (GS) is a tubulopathy caused by SLC12A3 gene mutations, which lead to hypokalaemic alkalosis, secondary hyperaldosteronism, hypomagnesaemia and hypocalciuria. Aim: The aim of this study was to assess the prevalence of SLC12A3 gene mutations in adult hypokalaemic patients; to compare the phenotype of homozygous, heterozygous and non-mutated patients; and to determine the efficiency of treatment. Methods: Clinical, biological and genetic data were recorded in 26 patients. Results: Screening for the SLC12A3 gene detected two mutations in 15 patients (six homozygous and nine compound heterozygous), one mutation in six patients and no mutation in five patients. There was no statistical difference in clinical symptoms at diagnosis between the three groups. Systolic blood pressure tended to be lower in patients with two mutations (PZ0.16). Hypertension was unexpectedly detected in four patients. Five patients with two mutated alleles and two with heterozygosity had severe manifestations of GS. Significant differences were observed between the three groups in blood potassium, chloride, magnesium, supine aldosterone, 24 h urine chloride and magnesium levels and in modification of the diet in renal disease. Mean blood potassium levels increased from 2.8G0.3, 3.5 G0.5 and 3.2G0.3 before treatment to 3.2G0.5, 3.7G0.6 and 3.7G0.3 mmol/l with treatment in groups with two (PZ0.003), one and no mutated alleles respectively. Conclusion: In adult patients referred for renal hypokalaemia, we confirmed the presence of mutations of the SLC12A3 gene in 80% of cases. GS was more severe in patients with two mutated alleles than in those with one or no mutated alleles. High blood pressure should not rule out the diagnosis, especially in older patients.

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“…The t nucleotide at position +2 bp of the donor splice site consensus sequence is invariant in eukaryotic sequences [24], and mutations in this +2-bp t nucleotide have previously been found in patients with renal disorders [6, 25]. These and other studies have also revealed that such mutations in the donor splice site regions may be associated with an accumulation of unspliced precursor mRNA, retention of incompletely spliced precursors or complete absence of transcripts, or the appearance of aberrantly processed mRNA from the use of alternatively normally occurring 5′ splice sites or cryptic splice sites [24].…”

Section: Resultsmentioning

confidence: 99%

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Reed²,

Williams³

et al. 2009

Nephron Physiol

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Background/Aims: Dent’s disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. Methods: Eighteen probands with Dent’s disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. Results: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. Conclusions: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease in this patient cohort.

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Novel mutations in theSLC12A3gene causing Gitelman's syndrome in Swedes

Abstract: In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.

Cited by 6 publications

References 24 publications

Cryo-EM structure of the human sodium-chloride cotransporter NCC

Cryo-EM structure of the human sodium-chloride cotransporter NCC

Phenotype–genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

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