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 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.
authors.affiliation: NeuroTherapeutics Research Institute and Department of Neurological Surgery, University of California, Davis School of Medicine, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hunsaker
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Greco
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
mesh_terms: D000368:Aged; D001921:Brain / Q000473:pathology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure*; D012333:RNA, Messenger / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D025801:Ubiquitin; C497683:FMR1 protein, human