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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
- Source :
- Genetics in Medicine. 13:392-399
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
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 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
- Subjects :
- 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
Subjects
Details
- ISSN :
- 10983600
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....e5329b31e7ea5eb42e7c81e8188f8ae6