Evidence map›Paper›PMID 39934873›Full record

ArticleOrphanet journal of rare diseases2025

Functional evaluation of novel compound heterozygous variants in SLC12A3 of Gitelman syndrome.

Na Wang, Yuanxing Yang, Xiong Tian, Hongjun Fu, Shuaishuai Chen, Juping Du, Mengyi Xu, Haixia He, Bo Shen, Jiaqin Xu

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Article in Orphanet journal of rare diseases, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

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4citing papers in PubMed
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1 · What the graph read from it

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3 · Its place in the literature

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4 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

10 authors.

Na WangDepartment of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China.
Yuanxing YangDepartment of Endocrinology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
Xiong TianDepartment of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
Hongjun FuDepartment of Endocrinology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
Shuaishuai ChenDepartment of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China.
Juping DuDepartment of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China.
Mengyi XuDepartment of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China.
Haixia HeDepartment of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China.
Bo Shen *Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China. shenb@enzemed.com.
Jiaqin Xu *Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, China. xujq6218@enzemed.com.

Funding

National Natural Science Foundation of China 82000774Natural Science Foundation of Zhejiang Province LTGD24H070001
6 · The paper itself

Abstract

backgroundGitelman syndrome (GS) is an inherited renal tubular disorder characterized by hypokalemic alkalosis and hypomagnesemia, due to biallelic pathogenic variants in the solute carrier family 12 member 3 (SLC12A3) gene encoding a sodium-chloride (Na-Cl) cotransporter (NCC). This work aimed at identifying SLC12A3 variants in the GS pedigree and reveal the effect of the mutations on protein structure and function.

methodsWhole-exome sequencing (WES) and Sanger sequencing were performed in the pedigree. Configuration prediction of two mutant NCC proteins were achieved using SWISS-MODEL. The SLC12A3 missense mutants were generated by site-specific mutagenesis, and the protein expression, location and Na

resultsGenetic analysis identified novel compound heterozygous SLC12A3 variants (c.718G > A/p.E240K and c.2675T > C/p.L892P) in the patient with typical GS phenotype. Both of her parents, elder brother and her son carried the heterozygous p.L892P variant, but only the elder brother exhibited mild hypokalemia. Bioinformatics tools predicted that both mutations were highly species conserved and pathogenic. The prediction of mutant protein indicated that p.E240K and p.L892P altered protein's secondary and three-dimensional (3D) structure and stability. Functional experiments revealed decreased protein expression and Na

conclusionOur study presents the genetic and functional evidence for the novel compound heterozygous loss-of-function variants in SLC12A3 that may synergistically cuase GS, and expands the mutation spectrum of SLC12A3 variants in patients with GS.

Indexed as

Gitelman SyndromeSolute Carrier Family 12, Member 3Exome SequencingFemaleHEK293 CellsHeterozygoteHumansMaleMutation, MissensePedigreeSLC12A3 protein, humanSolute Carrier Family 12, Member 3Gene mutationGitelman syndromeHypokalemiaLoss-of-functionSLC12A3

Identifiers

PMID39934873
PMCPMC11816502

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