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
| Autor: | Quang M. Bui, Elsdon Storey, Glynda J. Kinsella, Nicholas Trost, David E. Godler, Freya Gehling, Alison Venn, Katya Kotschet, David R. Thorburn, Howard R. Slater, Andrew Evans, David Francis, Paige Stimpson, Danuta Z. Loesch, Malcolm K. Horne |
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| Přispěvatelé: | Loesch, Danuta Z, Godler, David E, Evans, Andrew, Bui, Quang M, Gehling, Freya, Kotschet, Katya E, Trost, Nicholas, Storey, Elsdon, Stimpson, Paige, Kinsella, Glynda, Francis, David, Thorburn, David R, Venn, Alison, Slater, Howard R, Horne, Malcolm |
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Pathology Transcription Genetic Population Disease Motor Activity Biology DNA Mitochondrial Article Pathogenesis Fragile X Mental Retardation Protein Parkinsonian Disorders gray zone Internal medicine mitochondrial dysfunction medicine Humans RNA Messenger Allele Cognitive decline education Alleles Genetic Association Studies parkinsonism Genetics (clinical) Aged Aged 80 and over education.field_of_study Parkinsonism Middle Aged medicine.disease FMR1 nervous system diseases premutation Endocrinology Trinucleotide Repeat Expansion Trinucleotide repeat expansion |
| Zdroj: | Genetics in Medicine. 13:392-399 |
| ISSN: | 1098-3600 |
| DOI: | 10.1097/gim.0b013e3182064362 |
| Popis: | 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 non carriers 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 Ascores) 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 sub unit 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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