New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12

摘要: The increase in genome scanning data, derived from clinical genetics practice, is producing a wealth of information on human sequence variability. critical issue to identify if given nucleotide change results benign polymorphism or disease-causing mutation. We have focused one specific gene expression step, pre-mRNA processing, where we can functionally define the effect changes and turn patient's mutation shed light basic pre mRNA splicing mechanisms. Our show that several CFTR exon 12 induce variable extent skipping leads reduced levels normal transcripts. This case both natural mutations D565G G576A (the latter having previously considered neutral polymorphism) site-directed silent substitutions. demonstrate here this phenomenon due interference with new regulatory element named composite exonic (CERES). single substitutions at CERES cannot be predicted by neither SR matrices nor enhancer identification. recognition characterization abnormalities, caused variations elements, may represent frequent mechanism also relates phenotypic indicate even most looking an ignored as it affect process. Hence, appropriate functional assays should included genotype screenings distinguish between polymorphisms pathogenic mutations.