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DC Field | Value | Language |
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dc.contributor.author | Nethisinghe, S | - |
dc.contributor.author | Kesavan, M | - |
dc.contributor.author | Ging, H | - |
dc.contributor.author | Labrum, R | - |
dc.contributor.author | Polke, JM | - |
dc.contributor.author | Islam, S | - |
dc.contributor.author | Garcia-Moreno, H | - |
dc.contributor.author | Callaghan, MF | - |
dc.contributor.author | Cavalcanti, F | - |
dc.contributor.author | Pook, MA | - |
dc.contributor.author | Giunti, P | - |
dc.date.accessioned | 2021-12-01T14:09:16Z | - |
dc.date.available | 2021-12-01T14:09:16Z | - |
dc.date.issued | 2021-07-12 | - |
dc.identifier | 7507 | - |
dc.identifier.citation | Nethisinghe, S., Kesavan, M., Ging, H., Labrum, R., Polke, J. M., Islam, S., Garcia-Moreno, H., Callaghan, M.F., Cavalcanti, F., Pook, M. A. and Giunti, P. (2021) ‘Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner’, International Journal of Molecular Sciences, 22 (14), 7507, pp. 1-13. doi: 10.3390/ijms22147507. | en_US |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/23656 | - |
dc.description.abstract | Copyright: © 2021 by the authors. Friedreich’s ataxia (FRDA) is a comparatively rare autosomal recessive neurological disorder primarily caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene. The repeat expansion causes gene silencing that results in deficiency of the frataxin protein leading to mitochondrial dysfunction, oxidative stress and cell death. The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5′ and 3′ ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3′ interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5′ interruption, 3′ interruption, both 5′ and 3′ interruptions or lacking interruption. Those patients with 3′ interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3′ interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5′ and 3′ interruptions. This highlights the key role of interruptions at the 3′ end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient. | en_US |
dc.description.sponsorship | European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement number 242193/EFACTS; National Brain Appeal—Small Acorns Fund; The Wellcome Centre for Human Neuroimaging is supported by core funding from the Wellcome (203147/Z/16/Z); Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme; CRN; North Thames, National Institute for Health Research (NIHR). Medical Research Council (MR/N028767/1). | en_US |
dc.format.extent | 1 -13 (13) | - |
dc.format.medium | Electronic | - |
dc.language | en | - |
dc.language.iso | en_US | en_US |
dc.publisher | MDPI AG | en_US |
dc.rights | Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | Friedreich’s ataxia | en_US |
dc.subject | FRDA | en_US |
dc.subject | ataxia | en_US |
dc.subject | GAA repeat interruption | en_US |
dc.subject | triplet repeat primed PCR | en_US |
dc.subject | TP PCR | en_US |
dc.subject | frataxin | en_US |
dc.subject | FXN | en_US |
dc.title | Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.3390/ijms22147507 | - |
dc.relation.isPartOf | International Journal of Molecular Sciences | - |
pubs.issue | 14 | - |
pubs.publication-status | Published online | - |
pubs.volume | 22 | - |
dc.identifier.eissn | 1422-0067 | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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