| Abstract: | Alternative splicing is a regulated process that results in expression ofspecific mRNA and protein isoforms. Alternative splicing factors determine therelative abundance of each isoform. Here we focus on MBNL1, a splicing factormisregulated in the disease myotonic dystrophy. By altering the concentration ofMBNL1 in cells across a broad dynamic range, we show that different splicingevents require different amounts of MBNL1 for half-maximal response, and respondmore or less steeply to MBNL1. Motifs around MBNL1 exon 5 were studied to assesshow cis-elements mediate the MBNL1 dose-dependent splicingresponse. A framework was developed to estimate MBNL concentration usingsplicing responses alone, validated in the cell-based model, and applied tomyotonic dystrophy patient muscle. Using this framework, we evaluated theability of individual and combinations of splicing events to predict functionalMBNL concentration in human biopsies, as well as their performance as biomarkersto assay mild, moderate, and severe cases of DM. |
