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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  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:Medical and Health Sciences
Research Group:Public Health and Health Services
Research Field:Epidemiology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Venn, A (Professor Alison Venn)
ID Code:75522
Year Published:2011
Web of Science® Times Cited:34
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-02-02
Last Modified:2012-08-28
Downloads:0

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