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The skipping of constitutive exons in vivo induced by nonsense mutations
H C Dietz1, D Valle, C A Francomano
1Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Abstract:
Nonsense mutations create a premature signal for the termination of translation of messenger RNA. Such mutations have been observed to cause a severe reduction in the amount of mutant allele transcript or to generate a peptide truncated at the carboxyl end. Analysis of fibrillin transcript from a patient with Marfan syndrome revealed the skipping of a constitutive exon containing a nonsense mutation. Similar results were observed for two nonsense mutations in the gene encoding ornithine delta-aminotransferase from patients with gyrate atrophy. All genomic DNA sequences flanking these exons that are known to influence RNA splicing were unaltered, which suggests that nonsense mutations can alter splice site selection in vivo.
Insights
Nonsense mutations, which normally stop protein production early, can unexpectedly alter RNA splicing. This study shows these mutations can lead to exon skipping, impacting gene expression in diseases like Marfan syndrome.
Area of Science:
- Molecular Biology
- Genetics
- RNA Biology
Background:
- Nonsense mutations prematurely terminate messenger RNA (mRNA) translation.
- This typically results in reduced mRNA levels or truncated peptides.
- The impact of nonsense mutations on RNA splicing has been less understood.
Purpose of the Study:
- To investigate whether nonsense mutations can influence RNA splicing mechanisms.
- To determine if exon skipping is a consequence of specific nonsense mutations in disease contexts.
Main Methods:
- Analysis of fibrillin transcript from a Marfan syndrome patient.
- Examination of ornithine delta-aminotransferase gene transcripts from gyrate atrophy patients.
- Assessment of genomic DNA sequences flanking affected exons for splicing regulatory elements.
Main Results:
- Exon skipping was observed in fibrillin transcripts containing a nonsense mutation.
- Similar exon skipping was found in transcripts with nonsense mutations in the ornithine delta-aminotransferase gene.
- Genomic sequences known to affect RNA splicing were unaltered, suggesting the mutation itself influences splicing.
Conclusions:
- Nonsense mutations can alter splice site selection in vivo.
- This mechanism provides a novel explanation for the pathogenicity of certain nonsense mutations.
- Exon skipping induced by nonsense mutations contributes to genetic disease phenotypes.