Splicing defects caused by exonic mutations in PKD1 as a new mechanism of pathogenesis in autosomal dominant polycystic kidney disease

RNA Biology
Felix Claverie-MartinElena Ramos-Trujillo

Abstract

The correct splicing of precursor-mRNA depends on the actual splice sites plus exonic and intronic regulatory elements recognized by the splicing machinery. Surprisingly, an increasing number of examples reveal that exonic mutations disrupt the binding of splicing factors to these sequences or generate new splice sites or regulatory elements, causing disease. This contradicts the general assumption that missense mutations disrupt protein function and that synonymous mutations are merely polymorphisms. Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused mainly by mutations in the PKD1 gene. Recently, we analyzed a substantial number of PKD1 missense or synonymous mutations to further characterize their consequences on pre-mRNA splicing. Our results showed that one missense and 2 synonymous mutations induce significant defects in pre-mRNA splicing. Thus, it appears that aberrant splicing as a result of exonic mutations is a previously unrecognized cause of ADPKD.

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Citations

Jan 5, 2018·Genes·Lorena Suarez-ArtilesFelix Claverie-Martin
Jul 26, 2018·Journal of the American Society of Nephrology : JASN·Adrian Y TanHanna Rennert
Jul 14, 2018·European Journal of Human Genetics : EJHG·Elisa MolinariJohn A Sayer
May 16, 2017·Journal of Cellular and Molecular Medicine·María Álvarez-SattaDiana Valverde
May 17, 2017·Scientific Reports·Guillermo PousadaDiana Valverde
May 8, 2021·Biochemical Society Transactions·Miguel Barroso-GilJohn A Sayer

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Methods Mentioned

BETA
ISS
ISSs
in silico methods

Software Mentioned

SPANR
ESE
Rescue
NNSplice
ESEfinder
MaxEntScan
- ESE
Human Splicing Finder

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