Rare intranuclear inclusions in the brains of 3 older adult males with fragile X syndrome: Implications for the spectrum of fragile X-associated disorders

Michael R. Hunsaker, Claudia M. Greco, Flora Tassone, Robert F Berman, Rob Willemsen, Randi J Hagerman, Paul J Hagerman

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 insome 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.

Original languageEnglish (US)
Pages (from-to)462-469
Number of pages8
JournalJournal of Neuropathology and Experimental Neurology
Volume70
Issue number6
DOIs
StatePublished - Jun 2011

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Intranuclear Inclusion Bodies
Fragile X Syndrome
Fragile X Mental Retardation Protein
RNA
Brain
Trinucleotide Repeat Expansion
Parahippocampal Gyrus
Messenger RNA
Mutation
Mosaicism
5' Untranslated Regions
Dentate Gyrus
Reverse Transcription
Fluorescent Antibody Technique
Proteins
Alleles
Polymerase Chain Reaction
Genes

Keywords

  • Autism
  • FMR1
  • Fragile X syndrome
  • FXTAS
  • Neurodegeneration
  • Parkinson

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Rare intranuclear inclusions in the brains of 3 older adult males with fragile X syndrome: Implications for the spectrum of fragile X-associated disorders",
abstract = "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 insome 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.",
keywords = "Autism, FMR1, Fragile X syndrome, FXTAS, Neurodegeneration, Parkinson",
author = "Hunsaker, {Michael R.} and Greco, {Claudia M.} and Flora Tassone and Berman, {Robert F} and Rob Willemsen and Hagerman, {Randi J} and Hagerman, {Paul J}",
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AU - Tassone, Flora

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AU - Willemsen, Rob

AU - Hagerman, Randi J

AU - Hagerman, Paul J

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AB - 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 insome 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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