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Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman Syndrome.
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  • Xiaomeng Shi,
  • Qihua Liu,
  • Ruixiao Zhang,
  • Zhiying Liu,
  • Wencong Guo,
  • Sai Wang,
  • Xuyan Liu,
  • Yanhua Lang,
  • Irene Bottillo,
  • Leping Shao
Xiaomeng Shi
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China

Corresponding Author:17854278691@163.com

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Qihua Liu
Departmen of Material Supply Management the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Ruixiao Zhang
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Zhiying Liu
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Wencong Guo
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Sai Wang
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Xuyan Liu
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Yanhua Lang
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Irene Bottillo
Division of Medical Genetics Department of Molecular Medicine Sapienza University San Camillo-Forlanini Hospital Rome Italy
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Leping Shao
Department of Nephrology the Affiliated Qingdao Municipal Hospital of Qingdao University Qingdao China
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Abstract

Gitelman syndrome (GS) is a kind of salt-losing tubular disease, most of which is caused by SLC12A3 gene variants, and missense variants account for the majority. Recently, the phenomenon of exon skipping, in which exonic variants disrupt normal pre-mRNA splicing, has been related to a variety of diseases. The purpose of this study was to identify the effect of previously presumed missense SLC12A3 variants on pre-mRNA splicing using bioinformatics tools and minigenes. The results revealed that, among ten candidate variants, six variants (c.602G>A, c.602G>T, c.1667C>T, c.1925G>A, c.2548G>C and c.2549G>C) led to complete or incomplete exon skipping by affecting exonic splicing regulatory elements and/or disturbing canonical splice sites. It is worth mentioning that this is the largest study on pre-mRNA splicing of SLC12A3 exonic variants. In addition, our study emphasizes the importance of detecting splicing function at the mRNA level in GS and indicates that minigene analysis is a valuable tool for splicing functional assays of variants in vitro.