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

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  • Karsten Bork Nielsen, Denmark
  • Suzette Sørensen, Denmark
  • Luca Cartegni, Memorial Sloan-Kettering Cancer Center, United States
  • Thomas Juhl Corydon
  • Thomas Koed Doktor, Denmark
  • Lisbeth Dahl Schroeder, Denmark
  • Line Sinnathamby Reinert
  • Orly Elpeleg, Metabolic Disease Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  • Adrian R Krainer, Cold Spring Harbor Laboratory, United States
  • Niels Gregersen
  • Jørgen Kjems
  • Brage Storstein Andresen, Denmark
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 in the best-studied examples, the molecular mechanisms are not fully understood. Here, we use patient cells, model minigenes, and in vitro assays to show that a missense mutation in exon 5 of the medium-chain acyl-CoA dehydrogenase (MCAD) gene primarily causes exon skipping by inactivating a crucial exonic splicing enhancer (ESE), thus leading to loss of a functional protein and to MCAD deficiency. This ESE functions by antagonizing a juxtaposed exonic splicing silencer (ESS) and is necessary to define a suboptimal 3' splice site. Remarkably, a synonymous polymorphic variation in MCAD exon 5 inactivates the ESS, and, although this has no effect on splicing by itself, it makes splicing immune to deleterious mutations in the ESE. Furthermore, the region of MCAD exon 5 that harbors these elements is nearly identical to the exon 7 region of the survival of motor neuron (SMN) genes that contains the deleterious silent mutation in SMN2, indicating a very similar and finely tuned interplay between regulatory elements in these two genes. Our findings illustrate a mechanism for dramatic context-dependent effects of single-nucleotide polymorphisms on gene-expression regulation and show that it is essential that potential deleterious effects of mutations on splicing be evaluated in the context of the relevant haplotype.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Pages (from-to)416-432
Number of pages17
Publication statusPublished - 1 Mar 2007

    Research areas

  • Acyl-CoA Dehydrogenase, Cyclic AMP Response Element-Binding Protein, DNA Primers, Enhancer Elements, Genetic, Exons, Female, Genes, BRCA1, Humans, Immunity, Infant, Infant, Newborn, Lipid Metabolism, Inborn Errors, Molecular Sequence Data, Muscular Atrophy, Spinal, Mutation, Missense, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, RNA Splicing, RNA Stability, RNA-Binding Proteins, SMN Complex Proteins, Sequence Homology, Nucleic Acid, Silencer Elements, Transcriptional, Survival of Motor Neuron 2 Protein, Transcription, Genetic

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