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.

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.

• Authors: Danuta Z Loesch, David E Godler, Andrew Evans, Quang M Bui, Freya Gehling, Katya E Kotschet, Nicholas Trost, Elsdon Storey, Paige Stimpson, Glynda Kinsella, David Francis, David R Thorburn, Alison Venn, Howard R Slater, Malcolm Horne
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 13 Issue 5 Pg. 392-9 (May 2011) ISSN: 1530-0366 [Electronic] United States
• PMID: 21270637 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• RNA, Messenger
• Fragile X Mental Retardation Protein

Topics

• Aged
• Aged, 80 and over
• Alleles
• DNA, Mitochondrial (genetics, metabolism)
• Fragile X Mental Retardation Protein (genetics)
• Genetic Association Studies
• Humans
• Male
• Middle Aged
• Motor Activity (genetics)
• Parkinsonian Disorders (genetics)
• RNA, Messenger (genetics, metabolism)
• Transcription, Genetic (genetics)
• Trinucleotide Repeat Expansion (genetics)