R158Q and G212S, novel pathogenic compound heterozygous variants in SLC12A3 of Gitelman syndrome

doi:10.1007/s11684-022-0963-9

Frontiers of Medicine

2022, Vol. 16

Issue (6): 932-945 https://doi.org/10.1007/s11684-022-0963-9

本期目录

R158Q and G212S, novel pathogenic compound heterozygous variants in SLC12A3 of Gitelman syndrome

Zongyue Li^1,^2,³, Huixiao Wu^1,^2,³, Shuoshuo Wei^1,^2,³, Moke Liu^1,^2,³, Yingzhou Shi^1,^2,³, Mengzhu Li^1,^2,³, Ning Wang^2,^3,⁴, Li Fang^2,^3,⁴, Bo Xiang^2,^3,⁴, Ling Gao^1,^2,^3,⁴, Chao Xu^1,^2,^3,⁴(

), Jiajun Zhao^1,^2,^3,⁴(

)

¹. Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
². Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China
³. Shandong Institute of Endocrine and Metabolic Disease, Jinan 250021, China
⁴. Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China

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Abstract：

The dysfunction of Na⁺-Cl⁻ cotransporter (NCC) caused by mutations in solute carrier family12, member 3 gene (SLC12A3) primarily causes Gitelman syndrome (GS). In identifying the pathogenicity of R158Q and G212S variants of SLC12A3, we evaluated the pathogenicity by bioinformatic, expression, and localization analysis of two variants from a patient in our cohort. The prediction of mutant protein showed that p.R158Q and p.G212S could alter protein’s three-dimensional structure. Western blot showed a decrease of mutant Ncc. Immunofluorescence of the two mutations revealed a diffuse positive staining below the plasma membrane. Meanwhile, we conducted a compound heterozygous model—Ncc R156Q/G210S mice corresponding to human NCC R158Q/G212S. Ncc^R156Q/G210S mice clearly exhibited typical GS features, including hypokalemia, hypomagnesemia, and increased fractional excretion of K⁺ and Mg²⁺ with a normal blood pressure level, which made Ncc^R156Q/G210S mice an optimal mouse model for further study of GS. A dramatic decrease and abnormal localization of the mutant Ncc in distal convoluted tubules contributed to the phenotype. The hydrochlorothiazide test showed a loss of function of mutant Ncc in Ncc^R156Q/G210S mice. These findings indicated that R158Q and G212S variants of SLC12A3 were pathogenic variants of GS.

Key words： Gitelman syndrome mouse model compound heterozygous hypokalemia Slc12a3

收稿日期: 2022-05-26 出版日期: 2023-01-16

Corresponding Author(s): Chao Xu,Jiajun Zhao

引用本文:

. [J]. Frontiers of Medicine, 2022, 16(6): 932-945.
Zongyue Li, Huixiao Wu, Shuoshuo Wei, Moke Liu, Yingzhou Shi, Mengzhu Li, Ning Wang, Li Fang, Bo Xiang, Ling Gao, Chao Xu, Jiajun Zhao. R158Q and G212S, novel pathogenic compound heterozygous variants in SLC12A3 of Gitelman syndrome. Front. Med., 2022, 16(6): 932-945.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-022-0963-9
https://academic.hep.com.cn/fmd/CN/Y2022/V16/I6/932

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