Seemingly Neutral Polymorphic Variants May Confer Immunity to Splicing-Inactivating Mutations: A Synonymous SNP in Exon 5 of MCAD Protects from Deleterious Mutations in a Flanking Exonic Splicing Enhancer

摘要: The idea that point mutations in exons may affect splicing is intriguing and adds an additional layer of complexity when evaluating their possible effects. Even the best-studied examples, molecular mechanisms are not fully understood. Here, we use patient cells, model minigenes, vitro assays to show a missense mutation exon 5 medium-chain acyl-CoA dehydrogenase (MCAD) gene primarily causes skipping by inactivating crucial exonic enhancer (ESE), thus leading loss functional protein MCAD deficiency. This ESE functions antagonizing juxtaposed silencer (ESS) necessary define suboptimal 3′ splice site. Remarkably, synonymous polymorphic variation inactivates ESS, and, although this has no effect on itself, it makes immune deleterious ESE. Furthermore, region harbors these elements nearly identical 7 survival motor neuron (SMN) genes contains silent SMN2, indicating very similar finely tuned interplay between regulatory two genes. Our findings illustrate mechanism for dramatic context-dependent effects single-nucleotide polymorphisms gene-expression regulation essential potential be evaluated context relevant haplotype.