Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 70, Issue 6, Pages 462-469Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e31821d3194
Keywords
Autism; FMR1; Fragile X syndrome; FXTAS; Neurodegeneration; Parkinson
Categories
Funding
- National Institutes of Health (NIH) [HD036071, HD056031, NS044299, AG024488, HD002274, MH077554, MH078041, RL1 AG032115, RL1 NS062411, RL1 AG032119]
- National Fragile X Foundation
- Medical Investigation of Neurodevelopmental Disorders Institute
- National Institute of Dental and Craniofacial Research, NeuroTherapeutics Research Institute consortium [UL1 DE019583]
- National Center for Research Resources, a component of the NIH [UL1 RR024146]
- NIH Roadmap for Medical Research
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The FMR1 gene is polymorphic for the length of CGG trinucleotide repeat expansions in the 5' untranslated region. Premutation (55-200 CGG repeats) and full-mutation (>200 CGG repeats) alleles give rise to their respective disorders by different pathogenic mechanisms: RNA gain-of-function toxicity leads to fragile X-associated tremor/ataxia syndrome in the premutation range, and transcriptional silencing and absence of fragile X mental retardation protein (FMRP) lead to fragile X syndrome in the full-mutation range. However, for the latter, incomplete silencing and/or size-mosaicism might result in some contribution to the disease process from residual messenger RNA production. To address this possibility, we examined the brains of 3 cases of fragile X syndrome for the presence of intranuclear inclusions in the hippocampal dentate gyrus. We identified low levels (0.1%-1.3%) of intranuclear inclusions in all 3 cases. Quantitative reverse transcription-polymerase chain reaction for FMR1 messenger RNA and immunofluorescence for FMRP revealed low but detectable levels of both RNA and protein in the 3 cases, consistent with the presence of small numbers of inclusions. The intranuclear inclusions were only present in FMRP-immunoreactive cells. The small numbers of inclusions and very low levels of both FMR1 RNA and protein suggest that the clinical course in these 3 subjects would not have been influenced by contributions from RNA toxicity.
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