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

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...

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Published in:Frontiers of medicine 2022-12, Vol.16 (6), p.932-945
Main Authors: Li, Zongyue, Wu, Huixiao, Wei, Shuoshuo, Liu, Moke, Shi, Yingzhou, Li, Mengzhu, Wang, Ning, Fang, Li, Xiang, Bo, Gao, Ling, Xu, Chao, Zhao, Jiajun
Format: Article
Language:English
Subjects:
Animals
compound heterozygous
Gitelman syndrome
Gitelman Syndrome - genetics
Gitelman Syndrome - metabolism
Gitelman Syndrome - pathology
Humans
hypokalemia
Hypokalemia - genetics
Localization
Medicine
Medicine & Public Health
Mice
mouse model
Mutation
Phenotype
Research Article
Slc12a3
Solute Carrier Family 12, Member 3 - genetics
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Summary: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 Mg 2+ 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.
ISSN:2095-0217
2095-0225
DOI:10.1007/s11684-022-0963-9