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Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism
Citation
Loesch, DZ and Godler, DE and Evans, A and Bui, QM and Gehling, F and Kotschet, KE and Trost, N and Storey, E and Stimpson, P and Kinsella, G and Francis, D and Thorburn, DR and Venn, A and Slater, HR and Horne, M, Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism, Genetics in Medicine, 13, (5) pp. 392-399. ISSN 1098-3600 (2011) [Refereed Article]
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Copyright Statement
Copyright 2011 American College of Medical Genetics
DOI: doi:10.1097/GIM.0b013e3182064362
Abstract
Purpose: Our previous results showed that both gray zone and lower
end premutation range (40-85 repeats) fragile X mental retardation 1
(FMR1) alleles were more common among males with parkinsonism
than in the general population. This study aimed to determine whether
these alleles have a significant role in the manifestations and pathogenesis
of parkinsonian disorders. Methods: Detailed clinical assessment
and genetic testing were performed in 14 male carriers of premutation
and gray zone FMR1 alleles and in 24 noncarriers identified in a sample
of males with parkinsonism. Results: The premutation and gray zone
carriers presented with more severe symptoms than disease controls
matched for age, diagnosis, disease duration, and treatment. The Parkinson
disease (Unified Parkinson's Disease Rating Scale) motor score
and the measures of cognitive decline (Mini-Mental State Examination
and/or Addenbrooke's Cognitive Examination Final Revised Version A
scores) were significantly correlated with the size of the CGG repeat and
the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in
blood leukocytes. In addition, the carriers showed a significant depletion
of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit
1 mitochondrial gene in whole blood. Conclusion: Small CGG
expansion FMR1 alleles (gray zone and lower end premutation) play a
significant role in the development of the parkinsonian phenotype,
possibly through the cytotoxic effect of elevated sense and/or antisense
FMR1 transcripts involving mitochondrial dysfunction and leading to
progressive neurodegeneration.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | parkinsonism; premutation; gray zone; mitochondrial dysfunction; FMR1/ASFMR1/FMR4 |
| Research Division: | Health Sciences |
| Research Group: | Epidemiology |
| Research Field: | Epidemiology not elsewhere classified |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Clinical health not elsewhere classified |
| UTAS Author: | Venn, A (Professor Alison Venn) |
| ID Code: | 75522 |
| Year Published: | 2011 |
| Web of Science® Times Cited: | 61 |
| Deposited By: | Menzies Institute for Medical Research |
| Deposited On: | 2012-02-02 |
| Last Modified: | 2022-08-25 |
| Downloads: | 0 |
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