Rare Intranuclear Inclusions in the Brains of 3 Older Adult Males With Fragile X Syndrome: Implications for the Spectrum of Fragile X-Associated Disorders
Year: 2011
Type: article
Study design: Case Report
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 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.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: National Fragile X Foundation, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Dental and Craniofacial Research, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1064348956, G1290979756, G1398166898, Mouse Models of FXTAS: Defining Critical Periods and Molecular Targets, G2281616085, G2738306040, Development of targeted therapeutic agents for the treatment of FXTAS (2 of 6), G2944198674, G2973466140, G3306906556, Characterization and Treatment of CNS Abnormalities in Premutation Carriers (4 of, G360721996, G3746498070, G3777162036, Action tremor & dementia in male carriers of fragile X, G3982541408, G5091678919, Research in Intellectual and Developmental Disabilities, G5483064532, G5856486229, G6010579943, G6231962548, G7743356462, G802620026, G9000005258, G9000034030, G9000041384, G9000072478, G9000159814, G9000233244
OpenAlex ID: W2077820191