Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation
Language English Country Germany Media print-electronic
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
PubMed
27837218
DOI
10.1007/s00109-016-1484-2
PII: 10.1007/s00109-016-1484-2
Knihovny.cz E-resources
- Keywords
- Complex splicing aberration, De novo splice site, IDS, Pseudoexon, Splice site competition,
- MeSH
- Point Mutation MeSH
- Exons MeSH
- Glycoproteins genetics MeSH
- Introns MeSH
- Humans MeSH
- RNA, Messenger genetics MeSH
- RNA Splice Sites MeSH
- Adolescent MeSH
- Mucopolysaccharidosis II genetics MeSH
- Mutation MeSH
- RNA Splicing MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Glycoproteins MeSH
- IDS protein, human MeSH Browser
- RNA, Messenger MeSH
- RNA Splice Sites MeSH
UNLABELLED: Mutations affecting splicing underlie the development of many human genetic diseases, but rather rarely through mechanisms of pseudoexon activation. Here, we describe a novel c.1092T>A mutation in the iduronate-2-sulfatase (IDS) gene detected in a patient with significantly decreased IDS activity and a clinical diagnosis of mild mucopolysaccharidosis II form. The mutation created an exonic de novo acceptor splice site and resulted in a complex splicing pattern with multiple pseudoexon activation in the patient's fibroblasts. Using an extensive series of minigene splicing experiments, we showed that the competition itself between the de novo and authentic splice site led to the bypass of the authentic one. This event then resulted in activation of several cryptic acceptor and donor sites in the upstream intron. As this was an unexpected and previously unreported mechanism of aberrant pseudoexon inclusion, we systematically analysed and disproved that the patient's mutation induced any relevant change in surrounding splicing regulatory elements. Interestingly, all pseudoexons included in the mature transcripts overlapped with the IDS alternative terminal exon 7b suggesting that this sequence represents a key element in the IDS pre-mRNA architecture. These findings extend the spectrum of mechanisms enabling pseudoexon activation and underscore the complexity of mutation-induced splicing aberrations. KEY MESSAGE: Novel exonic IDS gene mutation leads to a complex splicing pattern. Mutation activates multiple pseudoexons through a previously unreported mechanism. Multiple cryptic splice site (ss) activation results from a bypass of authentic ss. Authentic ss bypass is due to a competition between de novo and authentic ss.
Center for Medical Genetics UZ Brussel and Vrije Universiteit Brussel 1090 Brussels Belgium
Central European Institute of Technology Masaryk University Brno Czech Republic
International Centre for Genetic Engineering and Biotechnology Trieste Italy
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