Exonic splicing silencer

An exonic splicing silencer (ESS) is a short region (usually 4-18 nucleotides) of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the pre-mRNA and contribute to constitutive and alternate splicing. To elicit the silencing affect, ESSs recruit proteins that will negatively affect the core splicing machinery.

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 intronic and exonic regions spliced in order to be translated. ESSs silence splice sites adjacent to them by interfering with the components of the core splicing complex, such as the snRNP's, U1 and U2. This causes proteins that negatively influence splicing to be recruited to the splicing machinery.

ESSs have four general roles:

Myotonic dystrophy (MD) is most noticeably caused by inheriting an unstable CTG triplet expansion in the DMPK gene. In healthy genotypes two isoforms of an insulin receptor mRNA transcript exist.The isoform IR-A lacks exon 11 and is expressed ubiquitously in cells. Isoform IR-B contains exon 11 and is expressed in cells of the liver, muscles, kidney, and adipocytes. In individuals with MD, IR-A is upregulated in high amounts in skeletal muscle leading to the disease phenotype.

The ESS nulceotide 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.

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).

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