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.
The aim of this study was to analyze the genetic variants of 51 Chinese patients with distal renal tubular acidosis (dRTA) and explore the correlation between their genotype and phenotype. Eight variants of SLC4A1, 19 variants of ATP6V0A4, and 16 variants of ATP6V1B1 have been identified, and of which 14 were novel ones. Eleven patients with autosomal dominant dRTA, and four patients with autosomal recessive dRTA were caused by genetic defects in SLC4A1; 18 and nine patients with recessive dRTA were resulted by defects in ATP6V0A4 and ATP6V1B1 respectively; no causal gene was identified in seven patients. Mutation frequency of SLC4A1 in Chinese populations was more common than Europeans. The incidence of deafness in ATP6V0A4 and ATP6V1B1 groups was 16.7% and 54.5%, respectively. The frequency of CKD in adults, children and infants was 100%, 51%, and 3%, separately. Our study will further expand the mutation spectrum of primary dRTA and provide valuable references to genetic counseling of Chinese populations.
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
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