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Identification of seven exonic variants in the SLC4A1 , ATP6V1B1 , and ATP6V0A4 genes that alter RNA splicing by minigene assay
Author(s) -
Zhang Ruixiao,
Chen Zeqing,
Song Qijing,
Wang Sai,
Liu Zhiying,
Zhao Xiangzhong,
Shi Xiaomeng,
Guo Wencong,
Lang Yanhua,
Bottillo Irene,
Shao Leping
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24246
Subject(s) - minigene , rna splicing , biology , exonic splicing enhancer , exon , alternative splicing , genetics , gene , exon skipping , intron , messenger rna , microbiology and biotechnology , rna
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 precursor messenger RNA (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, 7 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* and c.1572G>A, p.Pro524Pro) were identified to result in complete or incomplete exon skipping by either disruption of exonic splicing enhancers (ESEs) and generation of exonic splicing silencers, 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.