ESEfinder: A web resource to identify exonic splicing enhancers

Abstract

Point mutations frequently cause genetic diseases by disrupting the correct pattern of pre-mRNA splicing. The effect of a point mutation within a coding sequence is traditionally attributed to the deduced change in the corresponding amino acid. However, some point mutations can have much more severe effects on the structure of the encoded protein, for example when they inactivate an exonic splicing enhancer (ESE), thereby resulting in exon skipping. ESEs also appear to be especially important in exons that normally undergo alternative splicing. Different classes of ESE consensus motifs have been described, but they are not always easily identified. ESEfinder (http://exon.cshl.edu/ESE/) is a web-based resource that facilitates rapid analysis of exon sequences to identify putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements.

Figure 1

Pictograms (1) representing the functional-SELEX consensus ESE motifs. The height of each letter reflects the frequency of each nucleotide at a given position, after adjusting for background nucleotide composition. At each position, the nucleotides are shown from top to bottom in order of decreasing frequency; orange letters indicate above-background frequencies. For each motif, the threshold value and the highest possible score are provided.

Figure 2

Example of ESEfinder input and output windows. (A) Input window. Two query sequences, BRCA1 exon 18 and a single point mutation variant (E1694X) are shown. All four matrices and their default threshold values were selected. Additional information is available from the tab links. (B) Output window. High scores, tabulated under each SR protein, are listed. Note that an SF2/ASF high score (arrow) has been abrogated by the mutation. (C) Output window with complete list of scores. (D) Graphic output window. High scores are represented as color-coded bars. The height of each bar indicates the score value, and its width and placement on the x-axis represent the length of the motif (6–8 nt) and its position along the sequence.