FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS).
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently identified neurodegenerative disorder affecting older adult males with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. The principal clinical features of FXTAS include progressive intention tremor, gait ataxia, parkinsonism, and autonomic dysfunction. The disorder affects at least one-third of carrier males over 50 years of age and, with an estimated carrier frequency of approximately 1/800 males, is likely to be one of the most common heritable forms of tremor and ataxia among older adult males in the general population. Brains from all FXTAS cases examined to date (10/10) possess numerous ubiquitin-positive intranuclear inclusions in broad distribution throughout the cerebrum and brainstem. The absence of either the neurodegenerative disorder or inclusions among adults with fragile X syndrome (who lack the FMR1 protein), coupled with elevated FMR1 mRNA with expanded CGG repeats in premutation carriers, has led us to propose an RNA toxic gain-of-function model for FXTAS. Consistent with this model, we have now identified FMR1 mRNA within the intranuclear inclusions isolated from post-mortem (FXTAS) brain tissue.
Tassone
Flora
F
Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Davis, California 95616, USA.
Iwahashi
Christine
C
Hagerman
Paul J
PJ
D000368:Aged; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000378:metabolism*; D014202:Tremor / Q000235:genetics* / Q000378:metabolism
D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human