Nonclassical splicing mutations in the coding and noncoding regions of the XXXX Gene: maximum entropy estimates of splice junction strengths.

@entity1 @entity14050 @entity16 @entity377 @entity1129
@entity1129 ( @entity1129 ) is an @entity16 caused by mutations in the @entity14050 gene. Classical splicing mutations (type I) delete entire exons during pre-mRNA splicing. In this report, we describe nine examples of nonclassical splicing mutations in 12 @entity1129 @entity1 and compare cDNA changes to estimates of splice junction strengths based on maximum entropy modeling. These mutations fall into three categories: pseudoexon insertions (type II), single @entity377 changes within the exon (type III), and intronic changes that disrupt the conserved 3' splice sequence and lead to partial exon deletion (type IV). Four @entity1 with a previously reported type II (pseudoexon) mutation all shared a common founder haplotype. Three @entity1 with apparent missense or silent mutations actually had type III aberrant splicing and partial deletion of an exon. Five @entity1 had type IV mutations that could have been misinterpreted as classical splicing mutations. Instead, their mutations disrupt a splice site and use another AG splice site located nearby within the exon; they lead to partial deletions at the beginning of exons. These nonclassical splicing mutations create frameshifts that result in premature termination codons. Without screening cDNA or using accurate models of splice site strength, the consequences of these genomic mutations cannot be reliably predicted. This may lead to further misinterpretation of genotype-phenotype correlations and may subsequently impact upon gene-based therapeutic approaches.
