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.
Keywords: ADPKD; ESE; ESS; ISE; ISS; NMD; PKD1; RT-PCR; SR proteins; SRE; autosomal dominant polycystic kidney disease; disease-causing variant; exonic mutations; exonic splicing enhancer; exonic splicing silencer; intronic splicing enhancer; intronic splicing silencer; mRNA analysis; minigene assay; missense mutation; nonsense-mediated mRNA decay; pre-mRNA splicing; reverse-transcribed polymerase chain reaction; serine/arginine-rich proteins; splice site mutation; splicing regulatory element; synonymous mutation.