Loss of exon identity is a common mechanism of human inherited disease

It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inher...

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Bibliographic Details
Published in:Genome research 2011-10, Vol.21 (10), p.1563-1571
Main Authors: Sterne-Weiler, Timothy, Howard, Jonathan, Mort, Matthew, Cooper, David N, Sanford, Jeremy R
Format: Article
Language:English
Subjects:
Base Sequence
beta-Globins - biosynthesis
beta-Globins - genetics
Codon, Nonsense
Computer applications
Computer Simulation
Enhancers
Exon skipping
Exons
Gene polymorphism
Gene regulation
Genes, Reporter
Genetic Diseases, Inborn - genetics
HeLa Cells
Hereditary diseases
Heredity
Humans
Models, Genetic
mRNA processing
Mutation
Mutation, Missense
Polymorphism, Single Nucleotide
RNA Processing, Post-Transcriptional
RNA Splice Sites
RNA Splicing
Single-nucleotide polymorphism
Splicing
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Summary:It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inherited disease is still poorly understood. Here we use a top-down approach to determine rates of loss or gain of known human exonic splicing regulatory (ESR) sequences associated with either disease-causing mutations or putatively neutral single nucleotide polymorphisms (SNPs). We observe significant enrichment toward loss of ESEs and gain of ESSs among inherited disease-causing variants relative to neutral polymorphisms, indicating that exon skipping may play a prominent role in aberrant gene regulation. Both computational and biochemical approaches underscore the relevance of exonic splicing enhancer loss and silencer gain in inherited disease. Additionally, we provide direct evidence that both SRp20 (SRSF3) and possibly PTB (PTBP1) are involved in the function of a splicing silencer that is created de novo by a total of 83 different inherited disease mutations in 67 different disease genes. Taken together, we find that ~25% (7154/27,681) of known mis-sense and nonsense disease-causing mutations alter functional splicing signals within exons, suggesting a much more widespread role for aberrant mRNA processing in causing human inherited disease than has hitherto been appreciated.
ISSN:1088-9051
1549-5469
DOI:10.1101/gr.118638.110