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Identification of eight exonic variants in the SLC4A1, ATP6V1B1 and ATP6V0A4 gene that alter RNA splicing by minigene assay
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  • Ruixiao Zhang,
  • Zeqing Chen,
  • Qijing Song,
  • Sai Wang,
  • Zhiying Liu,
  • Xiangzhong Zhao,
  • Xiaomeng Shi,
  • Wencong Guo,
  • Yanhua Lang,
  • Irene Bottillo,
  • Leping Shao
Ruixiao Zhang
Qingdao Municipal Hospital Group
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Zeqing Chen
Fudan University
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Qijing Song
People's Hospital of Jimo District
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Sai Wang
Qingdao Municipal Hospital Group
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Zhiying Liu
Qingdao Municipal Hospital Group
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Xiangzhong Zhao
The Affiliated Hospital of Qingdao University
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Xiaomeng Shi
Qingdao Municipal Hospital Group
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Wencong Guo
The Affiliated Hospital of Qingdao University
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Yanhua Lang
Qingdao Municipal Hospital Group
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Irene Bottillo
IRCCS-Casa Sollievo della Sofferenza Hospital
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Leping Shao
Qingdao Municipal Hospital Group
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Abstract

Primary distal renal tubular acidosis (dRTA) is a rare tubular disease associated with variants in SLC4A1, ATP6V0A4, ATP6V1B1, FOXⅠ1 or WDR72 genes. Currently, there is growing evidence that all types of exonic variants can alter splicing regulatory elements, affecting the pre-mRNA splicing process. This study was to determine the consequences of variants associated with dRTA on pre-mRNA splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 15 candidate variants, 8 variants distributed in SLC4A1 (c.1765C>T, p.Arg589Cys), ATP6V1B1( c.368G>T, p.Gly123Val; c.370C>T, p.Arg124Trp; c.484G>T, p.Glu162* and c.1102G>A, p.Glu368Lys) and ATP6V0A4 genes (c.322C>T, p.Gln108*; c.1571C>T, p.Pro524Leu and c.1572G>A, p.Pro524Pro) were identified to result in whole or part of exon skipping by either disruption of ESEs and generation of ESSs, or interference with the recognition of the classic splicing site, or both. To our knowledge, this is the first study on pre-mRNA splicing of exonic variants in the dRTA-related genes. These results highlight the importance of assessing the effects of exonic variants at the mRNA level and suggest that minigene analysis is an effective tool for evaluating the effects of splicing on variants in vitro

Peer review status:UNDER REVIEW

27 Jan 2021Submitted to Human Mutation
28 Jan 2021Submission Checks Completed
28 Jan 2021Assigned to Editor
07 Feb 2021Reviewer(s) Assigned
24 Feb 2021Review(s) Completed, Editorial Evaluation Pending
27 Feb 2021Editorial Decision: Revise Major
02 Jun 20211st Revision Received
03 Jun 2021Submission Checks Completed
03 Jun 2021Assigned to Editor
03 Jun 2021Reviewer(s) Assigned
07 Jun 2021Review(s) Completed, Editorial Evaluation Pending