Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
PURPOSE: Gitelman syndrome (GS) is an autosomal recessive renal tubular disease that arises as a consequence of mutations in the SLC12A3 gene, which codes for an Na-Cl cotransporter (NCC) in distal renal tubules. This study was designed to explore the mutations associated with GS in an effort to more fully understand the molecular mechanisms governing GS.
METHODS: We analyzed SLC12A3 mutations in a pedigree including a 42-year-old male with GS as well as four related family members over three generations using Sanger and next generation sequencing approaches. We additionally explored the functional ramifications of identified mutations using both Xenopus oocytes and the HEK293T cell line.
RESULTS: We found that the subject with GS exhibited characteristic symptoms including sporadic thirst, fatigue, excess urination, and substantial hypokalemia and hypocalciuria, although magnesium levels were normal. Other analyzed subjects in this pedigree had normal laboratory findings and did not exhibit clear signs of GS. Sequencing analyses revealed that the GS subject exhibited a homozygous missense mutation (c.2874C > G, p.N958K) in exon 24 of SLC12A3. Both parents of this GS subject, as well as his older brother and daughter all exhibited heterozygous mutations at this same site. Functional analyses in Xenopus oocytes indicated that this mutated SLC12A3 gene encodes a protein which fails to mediate normal sodium transport, and when this mutant gene was expressed in HEK293T cells, we observed significant increases in endoplasmic reticulum (ER)-stress pathway activation.
CONCLUSION: The p.N958K mutation in exon 24 of SLC12A3 can trigger GS at least in part via enhancing ER stress responses.
Almanza,
Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications.
2019, Pubmed
Almanza,
Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications.
2019,
Pubmed Bao,
Genetic screening for Bartter syndrome and Gitelman syndrome pathogenic genes among individuals with hypertension and hypokalemia.
2019,
Pubmed Blanchard,
Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome.
2015,
Pubmed Chen,
A case of hypokalemia and proteinuria with a new mutation in the SLC12A3 Gene.
2018,
Pubmed Cipolletta,
Calcium Pyrophosphate Deposition Disease in a Patient with Familial Hypokalemia-Hypomagnesemia (Gitelman's-Syndrome): A Case Report - CPPD in Gitelman's syndrome.
2020,
Pubmed Cruz,
Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.
2001,
Pubmed Dimke,
Exploring the intricate regulatory network controlling the thiazide-sensitive NaCl cotransporter (NCC).
2011,
Pubmed Fanis,
A novel heterozygous duplication of the SLC12A3 gene in two Gitelman syndrome pedigrees: indicating a founder effect.
2019,
Pubmed Fulchiero,
Bartter Syndrome and Gitelman Syndrome.
2019,
Pubmed Graham,
TPR-containing proteins control protein organization and homeostasis for the endoplasmic reticulum.
2019,
Pubmed Halperin,
SEC31A mutation affects ER homeostasis, causing a neurological syndrome.
2019,
Pubmed Hotamisligil,
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.
2010,
Pubmed Jiang,
Clinical severity of Gitelman syndrome determined by serum magnesium.
2014,
Pubmed Knoers,
Gitelman syndrome.
2008,
Pubmed Kong,
Digenetic inheritance of SLC12A3 and CLCNKB genes in a Chinese girl with Gitelman syndrome.
2019,
Pubmed Kunchaparty,
Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome.
1999,
Pubmed
,
Xenbase Lai,
Endoplasmic reticulum stress: signaling the unfolded protein response.
2007,
Pubmed Lee,
The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress.
2005,
Pubmed Lü,
A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review.
2016,
Pubmed Moremen,
Vertebrate protein glycosylation: diversity, synthesis and function.
2012,
Pubmed Needham,
The thiazide-sensitive NaCl cotransporter is targeted for chaperone-dependent endoplasmic reticulum-associated degradation.
2011,
Pubmed Paredes,
Activity of the renal Na+-K+-2Cl- cotransporter is reduced by mutagenesis of N-glycosylation sites: role for protein surface charge in Cl- transport.
2006,
Pubmed
,
Xenbase Pathare,
Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC).
2018,
Pubmed Riveira-Munoz,
Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome.
2007,
Pubmed
,
Xenbase Schild,
A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system.
1995,
Pubmed
,
Xenbase Sinha,
Gitelman syndrome: novel mutation and long-term follow-up.
2012,
Pubmed Sriburi,
XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum.
2004,
Pubmed Subasinghe,
Novel mutation in the SLC12A3 gene in a Sri Lankan family with Gitelman syndrome & coexistent diabetes: a case report.
2017,
Pubmed Tosi,
Normal plasma total magnesium in Gitelman syndrome.
2004,
Pubmed Valdez-Flores,
Functionomics of NCC mutations in Gitelman syndrome using a novel mammalian cell-based activity assay.
2016,
Pubmed
,
Xenbase Wang,
Novel heterozygous missense mutation of SLC12A3 gene in Gitelman syndrome: A case report.
2019,
Pubmed Wang,
Mutation profile and treatment of Gitelman syndrome in Chinese patients.
2017,
Pubmed Wichmann,
An extracellular acidic cleft confers profound H+-sensitivity to epithelial sodium channels containing the δ-subunit in Xenopus laevis.
2019,
Pubmed
,
Xenbase Wolfson,
Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways.
2008,
Pubmed Xu,
Endoplasmic reticulum stress: cell life and death decisions.
2005,
Pubmed Yang,
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.
2007,
Pubmed
,
Xenbase Yoshida,
XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.
2001,
Pubmed Zeng,
Genetic Analysis of SLC12A3 Gene in Chinese Patients with Gitelman Syndrome.
2019,
Pubmed Zhou,
Complicated Gitelman syndrome and autoimmune thyroid disease: a case report with a new homozygous mutation in the SLC12A3 gene and literature review.
2018,
Pubmed
