PRE-MRNA SPLICING AND HUMAN DISEASE
Thao O, Jeremy Sanford.
University of California, Santa Cruz, Santa Cruz, CA.
The vast majority of protein coding information in human genes is separated by interrupting sequences called introns. Introns are removed post-transcriptionally from the precursor mRNA to generate a contiguous array of exons that constitutes the mRNA. Mutations near the 5' or 3' splice site can lead to aberrant splicing such as exon skipping or intron inclusion, which may play an underappreciated role in human disease. Computational and functional analyses suggest that hexamer mutations can cause human inherited disease resulting from aberrant mRNA processing. Previous work from the Sanford lab shows that mutation within the ACUAGG hexamer induced skipping of exons from several genes including, OPA1, PYGM, and TFR2. Our project focuses on testing putative splicing sensitive mutations in PINK1 and PARK2 that are associated with Parkinson disease. In vitro characterization of the splicing sensitivity of these disease-associated mutations will give us information about their clinical significance and may be helpful in managing treatment of patients and family members with inherited variants within these genes.