scholarly journals Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy

2019 ◽  
Vol 20 (13) ◽  
pp. 3365 ◽  
Author(s):  
Łukasz J. Sznajder ◽  
Maurice S. Swanson
Keyword(s):  
Myotonic Dystrophy ◽  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Foci ◽  
Repeat Expansions ◽  
Multivalent Interactions ◽  
Short Tandem

Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUGexp, CCUGexp) RNAs, respectively. These CUGexp and CCUGexp RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly.

scholarly journals RNA Gelation in Repeat Expansion Disorders

2017 ◽  
Author(s):  
Ankur Jain ◽  
Ronald D. Vale
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuromuscular Disorders ◽  
Cag Repeats ◽  
Live Cells ◽  
Critical Threshold ◽  
Rna Foci ◽  
Repeat Expansions ◽  
Nucleotide Repeats

Expansions of short nucleotide repeats in the protein coding and non-coding regions of >30 genes produce a variety of neurological and neuromuscular disorders including Huntington’s disease (CAG repeats), muscular dystrophy (CTG repeats) and amyotrophic lateral sclerosis (GGGGCC repeats) [1-3]. Expression of expanded repeats alone is sufficient to recapitulate disease pathology in animal models [4-6]. Repeat-containing transcripts accumulate in the nucleus as aberrant “RNA foci” [7-10] and sequester numerous RNA binding proteins [11,12], leading to a disruption of cellular homeostasis [13,14]. Interestingly, RNA foci, as well as the disease symptoms, only manifest at a critical threshold of nucleotide repeats: >30 for CAG/CTG expansions [1] and >7 for the GGGGCC expansion [15]. However, the reason for this characteristic threshold, as well as the molecular mechanism of foci formation, remain unresolved [16]. Here, we show that nucleotide repeat expansions in RNA create templates for multivalent Watson-Crick (CAG/CUG expansions) or Hoogsteen (GGGGCC expansion) base-pairing. These multivalent interactions cause purified RNAs containing repeat expansions to undergo a sol-gel transition and form micron-sized clusters. Reflecting an increase in the valency for intermolecular hybridization, the gelation of purified RNA only occurs above a critical number of trinucleotide or hexanucleotide repeats. These thresholds for in vitro RNA gelation are similar to those associated with manifestation of disease. By visualizing RNA in live cells, we show that nuclear foci form as a result of phase separation of the repeat-containing RNA and that these foci can be dissolved by agents that disrupt RNA gelation in vitro. Analogous to protein aggregation disorders, our results suggest that the sequence-specific gelation of RNAs could be a contributing factor to neurological disease.

scholarly journals Correction to: Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Indhu-Shree Rajan-Babu ◽  
Junran J. Peng ◽  
Readman Chiu ◽  
Patricia Birch ◽  
Madeline Couse ◽  
...  
Keyword(s):  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Screening Test ◽  
Genome Wide ◽  
Repeat Expansions ◽  
Short Tandem

scholarly journals Multivalent interactions with RNA drive RNA binding protein recruitment and dynamics in biomolecular condensates in Xenopus oocytes

2021 ◽  
Author(s):  
Sarah E Cabral ◽  
Kimberly Mowry
Keyword(s):  
Protein Interactions ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Dependent Manner ◽  
Binding Domains ◽  
Multivalent Interactions

RNA localization and biomolecular condensate formation are key biological strategies for organizing the cytoplasm and generating cellular and developmental polarity. While enrichment of RNAs and RNA-binding proteins (RBPs) is a hallmark of both processes, the functional and structural roles of RNA-RNA and RNA-protein interactions within condensates remain unclear. Recent work from our laboratory has shown that RNAs required for germ layer patterning in Xenopus oocytes localize in novel biomolecular condensates, termed Localization bodies (L-bodies). L-bodies are composed of a non-dynamic RNA phase enmeshed in a more dynamic protein-containing phase. However, the interactions that drive the biophysical characteristics of L-bodies are not known. Here, we test the role of RNA-protein interactions using an L-body RNA-binding protein, PTBP3, which contains four RNA-binding domains (RBDs). We find that binding of RNA to PTB is required for both RNA and PTBP3 to be enriched in L-bodies in vivo. Importantly, while RNA binding to a single RBD is sufficient to drive PTBP3 localization to L-bodies, interactions between multiple RRMs and RNA tunes the dynamics of PTBP3 within L-bodies. In vitro, recombinant PTBP3 phase separates into non-dynamic structures in an RNA-dependent manner, supporting a role for RNA-protein interactions as a driver of both recruitment of components to L-bodies and the dynamics of the components after enrichment. Our results point to a model where RNA serves as a concentration-dependent, non-dynamic substructure and multivalent interactions with RNA are a key driver of protein dynamics.

scholarly journals Short tandem repeat stutter model inferred from direct measurement of in vitro stutter noise

2019 ◽  
Vol 47 (5) ◽  
pp. 2436-2445 ◽  
Author(s):  
Ofir Raz ◽  
Tamir Biezuner ◽  
Adam Spiro ◽  
Shiran Amir ◽  
Lilach Milo ◽  
...  
Keyword(s):  
Direct Measurement ◽  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Short Tandem

scholarly journals Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing

2019 ◽  
Vol 37 (12) ◽  
pp. 1478-1481 ◽  
Author(s):  
Pay Giesselmann ◽  
Björn Brändl ◽  
Etienne Raimondeau ◽  
Rebecca Bowen ◽  
Christian Rohrandt ◽  
...  
Keyword(s):  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Nanopore Sequencing ◽  
Methylation State ◽  
Repeat Expansions ◽  
Short Tandem

Short Tandem Repeat Contractions during in vitro DNA Synthesis by Repeat-Binding Molecules

2021 ◽  
Author(s):  
Masaki Hagihara ◽  
Chikara Dohno ◽  
Kaoru Saito ◽  
Kazuhiro Sugimoto ◽  
Yuta Hishinuma ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Short Tandem

scholarly journals STRetch: detecting and discovering pathogenic short tandem repeat expansions

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Harriet Dashnow ◽  
Monkol Lek ◽  
Belinda Phipson ◽  
Andreas Halman ◽  
Simon Sadedin ◽  
...  
Keyword(s):  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Repeat Expansions ◽  
Short Tandem

scholarly journals An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sanjog R. Chintalaphani ◽  
Sandy S. Pineda ◽  
Ira W. Deveson ◽  
Kishore R. Kumar
Keyword(s):  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Fragile X ◽  
Cost Effective ◽  
Repeat Expansion ◽  
Main Body ◽  
Cgg Repeat ◽  
Long Read ◽  
Repeat Expansions ◽  
Short Tandem

Abstract Background Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington’s disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia. Main body STR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic ‘AAGGG’ repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of ‘CGG’ repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e.g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion. Conclusion We anticipate that long-read sequencing will rapidly transform the detection of short tandem repeat expansion disorders for both clinical diagnosis and gene discovery.

scholarly journals An integrative study on ribonucleoprotein condensates identifies scaffolding RNAs and reveals a new player in Fragile X-associated Tremor/Ataxia Syndrome

2018 ◽  
Author(s):  
Fernando Cid-Samper ◽  
Mariona Gelabert-Baldrich ◽  
Benjamin Lang ◽  
Nieves Lorenzo-Gotor ◽  
Riccardo Delli Ponti ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Untranslated Regions ◽  
Binding Partners ◽  
Integrative Study ◽  
Splicing Regulator ◽  
Repeat Expansions ◽  
Ataxia Syndrome

SummaryRecent evidence indicates that specific RNAs promote formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs).We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly-contacted RNAs are highly structured, have long untranslated regions (UTRs) and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3’ UTR that harbors CGG expansions implicated in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model we validated TRA2A-FRM1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post mortem human samples.Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of new therapeutic targets.

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