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.
Endocr Connect
2022 Jan 27;111:. doi: 10.1530/EC-21-0262.
Show Gene links
Show Anatomy links
Frequent SLC12A3 mutations in Chinese Gitelman syndrome patients: structure and function disorder.
Jiang L
,
Peng X
,
Zhao B
,
Zhang L
,
Xu L
,
Li X
,
Nie M
,
Chen L
.
???displayArticle.abstract???
Purposes: This study was conducted to identify the frequent mutations from reported Chinese Gitelman syndrome (GS) patients, to predict the three-dimensional structure change of human Na-Cl co-transporter (hNCC), and to test the activity of these mutations and some novel mutations in vitro and in vivo.
Methods: SLC12A3 gene mutations in Chinese GS patients previously reported in the PubMed, China National Knowledge Infrastructure, and Wanfang database were summarized. Predicted configurations of wild type (WT) and mutant proteins were achieved using the I-TASSER workplace. Six missense mutations (T60M, L215F, D486N, N534K, Q617R, and R928C) were generated by site-directed mutagenesis. 22Na+ uptake experiment was carried out in the Xenopus laevisoocyte expression system. In the study, 35 GS patients and 20 healthy volunteers underwent the thiazide test.
Results: T60M, T163M, D486N, R913Q, R928C, and R959frameshift were frequent SLC12A3 gene mutations (mutated frequency >3%) in 310 Chinese GS families. The protein's three-dimensional structure was predicted to be altered in all mutations. Compared with WT hNCC, the thiazide-sensitive 22Na+ uptake was significantly diminished for all six mutations: T60M 22 ± 9.2%, R928C 29 ± 12%, L215F 38 ± 14%, N534K 41 ± 15.5%, Q617R 63 ± 22.1%, and D486N 77 ± 20.4%. In thiazide test, the net increase in chloride fractional excretion in 20 healthy controls was significantly higher than GS patients with or without T60M or D486N mutations.
Conclusions: Frequent mutations (T60M, D486N, and R928C) and novel mutations (L215F, N534K, and Q617R) lead to protein structure alternation and protein dysfunction verified by 22Na+ uptake experiment in vitro and thiazide test on the patients.
Amir Shaghaghi,
The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease.
2017, Pubmed,
Xenbase
Amir Shaghaghi,
The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease.
2017,
Pubmed
,
Xenbase
Colussi,
A thiazide test for the diagnosis of renal tubular hypokalemic disorders.
2007,
Pubmed
Colussi,
Abnormal reabsorption of Na+/CI- by the thiazide-inhibitable transporter of the distal convoluted tubule in Gitelman's syndrome.
1997,
Pubmed
Corpe,
Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice.
2010,
Pubmed
De Jong,
Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman's syndrome.
2002,
Pubmed
,
Xenbase
Fujimura,
Clinical and Genetic Characteristics in Patients With Gitelman Syndrome.
2019,
Pubmed
Glaudemans,
Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome.
2012,
Pubmed
,
Xenbase
Ji,
Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
2008,
Pubmed
Jiang,
Clinical severity of Gitelman syndrome determined by serum magnesium.
2014,
Pubmed
Jiang,
NORMOMAGNESEMIC GITELMAN SYNDROME PATIENTS EXHIBIT A STRONGER REACTION TO THIAZIDE THAN HYPOMAGNESEMIC PATIENTS.
2015,
Pubmed
Joo,
Reduced urinary excretion of thiazide-sensitive Na-Cl cotransporter in Gitelman syndrome: preliminary data.
2007,
Pubmed
Kunchaparty,
Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome.
1999,
Pubmed
,
Xenbase
Lin,
Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome.
2005,
Pubmed
Lin,
Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter.
2004,
Pubmed
Liu,
Genotype/Phenotype Analysis in 67 Chinese Patients with Gitelman's Syndrome.
2016,
Pubmed
Ma,
Genetic Features of Chinese Patients with Gitelman Syndrome: Sixteen Novel SLC12A3 Mutations Identified in a New Cohort.
2016,
Pubmed
Maki,
Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.
2004,
Pubmed
Mastroianni,
Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3).
1996,
Pubmed
Monroy,
Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction.
2000,
Pubmed
,
Xenbase
Moreno,
A single nucleotide polymorphism alters the activity of the renal Na+:Cl- cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity.
2004,
Pubmed
,
Xenbase
Peng,
Value of Chloride Clearance Test in Differential Diagnosis of Gitelman Syndrome.
2016,
Pubmed
Peng,
Increased urinary prostaglandin E2 metabolite: A potential therapeutic target of Gitelman syndrome.
2017,
Pubmed
Peng,
Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients.
2018,
Pubmed
Qin,
Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome.
2009,
Pubmed
Riveira-Munoz,
Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome.
2007,
Pubmed
,
Xenbase
Sabath,
Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease.
2004,
Pubmed
,
Xenbase
Shao,
High-frequency variant p.T60M in NaCl cotransporter and blood pressure variability in Han Chinese.
2012,
Pubmed
Soreq,
Xenopus oocyte microinjection: from gene to protein.
1992,
Pubmed
,
Xenbase
Tseng,
Genotype, phenotype, and follow-up in Taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation.
2012,
Pubmed
Tsukamoto,
Possible discrimination of Gitelman's syndrome from Bartter's syndrome by renal clearance study: report of two cases.
1995,
Pubmed
Tu,
Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid.
2015,
Pubmed
Vargas-Poussou,
Spectrum of mutations in Gitelman syndrome.
2011,
Pubmed
Wang,
Mutation profile and treatment of Gitelman syndrome in Chinese patients.
2017,
Pubmed
Yang,
Phosphorylation regulates NCC stability and transporter activity in vivo.
2013,
Pubmed
Yang,
Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome.
2010,
Pubmed
Yang,
I-TASSER server: new development for protein structure and function predictions.
2015,
Pubmed
Yuan,
Glucose tolerance and insulin responsiveness in Gitelman syndrome patients.
2017,
Pubmed
Zeng,
Genetic Analysis of SLC12A3 Gene in Chinese Patients with Gitelman Syndrome.
2019,
Pubmed
Zhang,
COFACTOR: improved protein function prediction by combining structure, sequence and protein-protein interaction information.
2017,
Pubmed
