Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation

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 activi...

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Published in:	Journal of molecular medicine (Berlin, Germany) Vol. 95; no. 3; pp. 299 - 309
Main Authors:	Grodecká, L., Kováčová, T., Kramárek, M., Seneca, S., Stouffs, K., De Laet, C., Majer, F., Kršjaková, T., Hujová, P., Hrnčířová, K., Souček, P., Lissens, W., Buratti, E., Freiberger, Tomas
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2017 Springer Nature B.V
Subjects:	Adolescent Biomedical and Life Sciences Biomedicine Exons Glycoproteins - genetics Human Genetics Humans Internal Medicine Introns Male Molecular Medicine Mucopolysaccharidosis II - genetics Mutation Original Article Point Mutation RNA Splice Sites RNA Splicing RNA, Messenger - genetics Complex splicing aberration Pseudoexon De novo splice site Splice site competition IDS
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Summary:	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.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0946-2716 1432-1440
DOI:	10.1007/s00109-016-1484-2