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From disease modelling to personalised therapy in patients with CEP290 mutations

Elisa Molinari1, Shalabh Srivastava1, John A Sayer1,2

  • 1Institute of Genetic Medicine, Newcastle University, Newcastle, NE1 3BZ, UK.

F1000Research
|July 11, 2017
PubMed

Insights

Nonsense-mediated decay usually removes faulty transcripts. However, this study examines altered exon usage in CEP290 transcripts, offering insights into genetic disease severity and potential therapies.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Premature termination codons (PTCs) are a frequent cause of inherited genetic disorders.
  • Nonsense-mediated decay (NMD) is a cellular surveillance pathway that degrades transcripts with PTCs.
  • CEP290 ciliopathies are a class of genetic diseases linked to mutations in the CEP290 gene.

Purpose of the Study:

  • To investigate alternative exon usage in CEP290 transcripts, distinct from NMD.
  • To explore the relationship between altered exon usage and disease severity in CEP290 ciliopathies.
  • To assess the potential for therapeutic strategies targeting exon usage in genetic diseases.

Main Methods:

  • Analysis of CEP290 transcript variants.
  • Examination of exon skipping and inclusion events.
  • Correlation of transcript changes with clinical data from CEP290 ciliopathy patients.

Main Results:

  • Observed alterations in CEP290 transcript structure due to changes in exon usage, not solely NMD.
  • Demonstrated a link between specific exon usage patterns and disease severity in CEP290 ciliopathies.
  • Highlighted the potential of modeling exon usage for predicting disease outcomes.

Conclusions:

  • Altered exon usage is a significant mechanism affecting CEP290 function in genetic diseases.
  • Understanding exon usage patterns can aid in predicting disease severity and guiding therapeutic development.
  • Targeting exon usage represents a potential future therapeutic avenue for genetic disorders caused by PTCs.
Keywords:
Cep290Joubert syndromeLeber congential amaurosisexon-skippinggenetic pleiotropynephronophthisissplicing

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