Abstract
Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases. When transcripts containing these changes are generated, they are usually rapidly removed by the cell through the process of nonsense-mediated decay. Here we discuss observed changes in transcripts of the centrosomal protein CEP290 resulting not from degradation, but from changes in exon usage. We also comment on a landmark paper (Drivas et al. Sci Transl Med. 2015) where modelling this process of exon usage may be used to predict disease severity in CEP290 ciliopathies, and how understanding this process may potentially be used for therapeutic benefit in the future.
Highlights
Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases
The compound heterozygous mutations described in a family with Leber congenital amaurosis (LCA) by Littink et al included a novel premature termination codon in exon 7 (c.451C>T, p.Arg151*)
The genetic pleiotropy exhibited in patients with CEP290 mutations may be explained in part by the differential ability of nonsenseassociated altered splicing (NAS) to give rise to a functional protein in the event of a premature termination codon being generated
Summary
Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases. Mechanisms of aberrant transcript removal Nonsense mutations are changes to the coding sequence of a gene, which lead to a termination (stop) codon being coded for in place of an amino acid, giving rise to a truncated protein.
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