Exonic splicing silencer
An exonic splicing silencer (ESS) is a short region (usually 4-18 nucleotides)
Mechanism of action
Exonic splicing silencers work by inhibiting the splicing of pre-mRNA strands or promoting exon skipping. The single stranded pre-mRNA molecules need to have their
ESSs have four general roles:[2]
- inhibiting exon inclusion
- inhibiting intron retention
- regulating alternative 5' splice site usage
- regulating alternative 3' splice site usage
Role in genetic diseases
Myotonic dystrophy
The ESS nucleotide sequence exists within intron 10 and is thought to be dependent on the CUG triplet repeat in order to silence the splicing of exon 11. Silencing exon 11 splicing leads to the increased transcription of the IR-A isoform.[4]
Cystic fibrosis
Mutations in the CFTR gene are responsible for causing cystic fibrosis. A particular mutation occurs in the CFTR pre-mRNA and leads to the exclusion of exon 9, mRNA lacking this exon folds a truncated protein (a protein shortened by a mutation).[4]
Exclusion of exon 9 is mediated by a polymorphic locus with variable TG repeats and stretches of T nucleotides – this is abbreviated as (TG)mT(n). This locus is an exonic splicing silencer and is located upstream of the exon 9 splice site (site 3c). The silencing is related to the high number of TG repeats and decreased stretches of T repeats (T tracts). A combination of both these factors is shown to increase levels of exon skipping.[4]
The
Spinal muscular atrophy
Spinal muscular atrophy is caused by the homozygous loss of the SMN1 gene. Humans have two isoforms of the SMN (survival motor neuron) gene, SMN1 and SMN2. The SMN1 gene produces a complete transcript, while SMN2 produces a transcript without exon 7 which results in a truncated protein.[4]
The ESS that contributes to the disease phenotype is the UAGACA nucleotide sequence. This sequence arises when a C-to-T mutation occurs at position +6 in exon 7 of the SMN2 gene. This transition point mutation leads to the exclusion of exon 7 from the mRNA transcript, it is also the only difference between the SMN2 and SMN1 gene.[4]
The UAGACA ESS is thought to work by disrupting an exonic splicing enhancer and attracting proteins that inhibit splicing by binding sequences on exon 7.[4]
Ataxia telangiectasia
Mutations in the