Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by expansion of 55-200 CGG repeats in the 5'-UTR of the FMR1 gene. FXTAS is characterized by action tremor, gait ataxia and impaired executive cognitive functioning. It has been proposed that FXTAS is caused by titration of RNA-binding proteins by the expanded CGG repeats. Sam68 is an RNA-binding protein involved in alternative splicing regulation and its ablation in mouse leads to motor coordination defects. Here, we report that mRNAs containing expanded CGG repeats form large and dynamic intranuclear RNA aggregates that recruit several RNA-binding proteins sequentially, first Sam68, then hnRNP-G and MBNL1. Importantly, Sam68 is sequestered by expanded CGG repeats and thereby loses its splicing-regulatory function. Consequently, Sam68-responsive splicing is altered in FXTAS patients. Finally, we found that regulation of Sam68 tyrosine phosphorylation modulates its localization within CGG aggregates and that tautomycin prevents both Sam68 and CGG RNA aggregate formation. Overall, these data support an RNA gain-of-function mechanism for FXTAS neuropathology, and suggest possible target routes for treatment options.
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PMID:Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. 2018 22

Expansion of repeated sequences in non-coding regions of different genes causes a number of inherited diseases including myotonic dystrophies, Huntington disease-like 2, Fragile X tremor/ataxia syndrome and spinocerebellar ataxia 8, 10, 12, 31. Involvement of an RNA gain-of-function mechanism in pathological case has been described and studied in-depth in myotonic dystrophy type 1 (DM1). This inherited neuromuscular disorder is caused by a (CTG)n >50 expansion in the 3' non-coding region of the dystrophia myotonica-protein kinase (DMPK) gene. Expanded CUG transcripts (CUGexp-RNAs) are sequestered in the nucleus within small aggregates and interfere with the regulatory splicing activities of MBNL1 and CELF1 RNA-binding proteins, leading to the misregulation of the alternative splicing of several transcripts. Despite the relevance of aberrant splicing events in this complex pathology, the CUGexp-RNAs trans-dominant effects alter other splicing-independent processes that may also contribute to DM1 pathogenesis. This review will focus on toxic RNA gain-of-function as a pathologic mechanism for DM1 and other repeat expansion disorders.
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PMID:Gain of RNA function in pathological cases: Focus on myotonic dystrophy. 2176 92