Nucleic Acids Research Advance Access originally published online on June 18, 2007
Nucleic Acids Research 2007 35(13):4369-4383; doi:10.1093/nar/gkm447
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Nucleic Acids Research, 2007, Vol. 35, No. 13 4369-4383
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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RNA structure is a key regulatory element in pathological ATM and CFTR pseudoexon inclusion events
International Centre for Genetic Engineering and Biotechnology (ICGEB) 34012 Trieste, Italy
*To whom correspondence should be addressed. Tel: +39-040-3757337; Fax: +39-040-3757361; Email: baralle{at}icgeb.org
Received March 29, 2007. Revised May 18, 2007. Accepted May 18, 2007.
Genomic variations deep in the intronic regions of pre-mRNA molecules are increasingly reported to affect splicing events. However, there is no general explanation why apparently similar variations may have either no effect on splicing or cause significant splicing alterations. In this work we have examined the structural architecture of pseudoexons previously described in ATM and CFTR patients. The ATM case derives from the deletion of a repressor element and is characterized by an aberrant 5'ss selection despite the presence of better alternatives. The CFTR pseudoexon instead derives from the creation of a new 5'ss that is used while a nearby pre-existing donor-like sequence is never selected. Our results indicate that RNA structure is a major splicing regulatory factor in both cases. Furthermore, manipulation of the original RNA structures can lead to pseudoexon inclusion following the exposure of unused 5'ss already present in their wild-type intronic sequences and prevented to be recognized because of their location in RNA stem structures. Our data show that intrinsic structural features of introns must be taken into account to understand the mechanism of pseudoexon activation in genetic diseases. Our observations may help to improve diagnostics prediction programmes and eventual therapeutic targeting.
Present address: Marzena A. Lewandowska, Children's Memorial Research Centre, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza #211, Chicago, IL 60614, USA
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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