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Title: Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy
Authors: Clelland, Allyson Kara
Bales, Alexandra Beatrice Elizabeth
Sleeman, Judith Elizabeth
Keywords: snRNPs
SMA
SMN
nucleus
QH301 Biology
Issue Date: 1-Jun-2012
Citation: Clelland , A K , Bales , A B E & Sleeman , J E 2012 , ' Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy ' Journal of Cell Science , vol 125 , no. 11 , pp. 2626-2637 .
Abstract: It is becoming increasingly clear that defects in RNA metabolism can lead to disease. Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from insufficient amounts of survival motor neuron (SMN) protein. SMN is required for the biogenesis of small nuclear ribonucleoproteins (snRNPs): essential components of the spliceosome. Splicing abnormalities have been detected in models of SMA but it is unclear how lowered SMN affects the fidelity of pre-mRNA splicing. We have examined the dynamics of mature snRNPs in cells depleted of SMN and demonstrated that SMN depletion increases the mobility of mature snRNPs within the nucleus. To dissect the molecular mechanism by which SMN deficiency affects intranuclear snRNP mobility, we employed a panel of inhibitors of different stages of pre-mRNA processing. This in vivo modelling demonstrates that snRNP mobility is altered directly as a result of impaired snRNP maturation. Current models of nuclear dynamics predict that subnuclear structures, including the spliceosome, form by self-organization mediated by stochastic interactions between their molecular components. Thus, alteration of the intranuclear mobility of snRNPs provides a molecular mechanism for splicing defects in SMA.
Version: Postprint
Description: This work was funded by the Wellcome Trust (grant ID WT078810MA)
Status: Peer reviewed
URI: http://hdl.handle.net/10023/2743
DOI: http://dx.doi.org/10.1242/jcs.096867
ISSN: 0021-9533
Type: Journal article
Rights: © 2012. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.
Appears in Collections:University of St Andrews Research
Biology Research
Biomedical Sciences Research Complex (BSRC) Research
Institute of Behavioural and Neural Sciences Research



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