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Cells
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Noncoding Repeat Expansion Diseases: Molecular Mechanisms and Therapeutics
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Noncoding Repeat Expansion Diseases: Molecular Mechanisms and Therapeutics

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 May 2023) | Viewed by 7020

Special Issue Editor

Dr. Isabel Silveira

E-Mail Website
Guest Editor
Genetics of Cognitive Dysfunction Laboratory, i3S- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
Interests: non-coding repeat expansions; neurodegenerative diseases; spinocerebellar ataxias; RNA-mediated toxicity; gene mapping; gene identification; molecular diagnosis; pentanucleotide repeat insertion; DAB1 gene; SCA37

Special Issue Information

Dear Colleagues, 

More than 50 inherited diseases are caused by unstable nucleotide repeat expansions. The nucleotide repeat motif varies in size from 3 to 12 base pairs, which in expanded chromosomes can range from 11 to over 10,000 copies. Most nucleotide repeat expansion tracts are located in gene non-coding regions. The expansion of these repeats causes neurodevelopmental, neuromuscular or neurodegenerative disease by a diversity of mechanisms, affecting several tissues and organs. To each of these conditions, there is associated a highly variable interindividual and interfamilial clinical presentation. The number of copies of the expanded repeat can determine the pathological mechanism and consequently the condition present in each expansion carrier. The purity or interrupted nature of the repeat sequence also influences disease manifestation. 

In non-coding gene regions, nucleotide repeat expansions can lead to epigenetic alterations with transcriptional repression due to CpG methylation of the repeat in fragile X syndrome, or histone hypermethylation of the disease gene in Friedreich ataxia. Expanded RNA repeats are toxic by a complex mechanism involving the formation of RNA foci that recruit RNA-binding proteins, originating alternative mis-splicing of multiple genes or/and by leading to repeat-associated non-AUG translation. 

The purpose of this Special Issue is to host both original contributions and review articles on the current molecular understanding of nucleotide repeat expansion diseases and related molecular therapies. 

Dr. Isabel Silveira
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nucleotide repeat expansion identification
  • repeat size instability
  • repeat sequence interruption
  • clinical heterogeneity
  • epigenetic modifications
  • protein loss-of-function
  • RNA gain-of-function
  • repeat-associated non-AUG translation
  • molecular diagnosis
  • molecular therapy

Published Papers (3 papers)

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Review

16 pages, 1554 KiB  
Review
Familial Adult Myoclonus Epilepsy: A Non-Coding Repeat Expansion Disorder of Cerebellar–Thalamic–Cortical Loop
by Claudia Cuccurullo, Pasquale Striano and Antonietta Coppola
Cells 2023, 12(12), 1617; https://doi.org/10.3390/cells12121617 - 13 Jun 2023
Cited by 2 | Viewed by 1357
Abstract
Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3–q24.1), FAME 2 (2p11.1–q12.1), FAME3 (5p15.31–p15.1), and FAME4 (3q26.32–3q28). To date, it is known that the genetic [...] Read more.
Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3–q24.1), FAME 2 (2p11.1–q12.1), FAME3 (5p15.31–p15.1), and FAME4 (3q26.32–3q28). To date, it is known that the genetic mechanism underlying FAME consists of the expansion of similar non-coding pentanucleotide repeats, TTTCA and TTTTA, in different genes. FAME is characterized by cortical tremor and myoclonus usually manifesting within the second decade of life, and infrequent seizures by the third or fourth decade. Cortical tremor is the core feature of FAME and is considered part of a spectrum of cortical myoclonus. Neurophysiological investigations as jerk-locked back averaging (JLBA) and corticomuscular coherence analysis, giant somatosensory evoked potentials (SEPs), and the presence of long-latency reflex I (or C reflex) at rest support cortical tremor as the result of the sensorimotor cortex hyperexcitability. Furthermore, the application of transcranial magnetic stimulation (TMS) protocols in FAME patients has recently shown that inhibitory circuits are also altered within the primary somatosensory cortex and the concomitant involvement of subcortical networks. Moreover, neuroimaging studies and postmortem autoptic studies indicate cerebellar alterations and abnormal functional connectivity between the cerebellum and cerebrum in FAME. Accordingly, the pathophysiological mechanism underlying FAME has been hypothesized to reside in decreased sensorimotor cortical inhibition through dysfunction of the cerebellar–thalamic–cortical loop, secondary to primary cerebellar pathology. In this context, the non-coding pentameric expansions have been proposed to cause cerebellar damage through an RNA-mediated toxicity mechanism. The elucidation of the underlying pathological mechanisms of FAME paves the way to novel therapeutic possibilities, such as RNA-targeting treatments, possibly applicable to other neurodegenerative non-coding disorders. Full article
(This article belongs to the Special Issue Noncoding Repeat Expansion Diseases: Molecular Mechanisms and Therapeutics)
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18 pages, 2455 KiB  
Review
Advances in Nucleotide Repeat Expansion Diseases: Transcription Gets in Phase
by Ana S. Figueiredo, Joana R. Loureiro, Sandra Macedo-Ribeiro and Isabel Silveira
Cells 2023, 12(6), 826; https://doi.org/10.3390/cells12060826 - 7 Mar 2023
Cited by 3 | Viewed by 2759
Abstract
Unstable DNA repeat expansions and insertions have been found to cause more than 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. One of the main hallmarks of repeat expansion diseases is the formation of abnormal RNA or protein aggregates in the neuronal cells of affected [...] Read more.
Unstable DNA repeat expansions and insertions have been found to cause more than 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. One of the main hallmarks of repeat expansion diseases is the formation of abnormal RNA or protein aggregates in the neuronal cells of affected individuals. Recent evidence indicates that alterations of the dynamic or material properties of biomolecular condensates assembled by liquid/liquid phase separation are critical for the formation of these aggregates. This is a thermodynamically-driven and reversible local phenomenon that condenses macromolecules into liquid-like compartments responsible for compartmentalizing molecules required for vital cellular processes. Disease-associated repeat expansions modulate the phase separation properties of RNAs and proteins, interfering with the composition and/or the material properties of biomolecular condensates and resulting in the formation of abnormal aggregates. Since several repeat expansions have arisen in genes encoding crucial players in transcription, this raises the hypothesis that wide gene expression dysregulation is common to multiple repeat expansion diseases. This review will cover the impact of these mutations in the formation of aberrant aggregates and how they modify gene transcription. Full article
(This article belongs to the Special Issue Noncoding Repeat Expansion Diseases: Molecular Mechanisms and Therapeutics)
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20 pages, 1559 KiB  
Review
Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions
by Nan Zhang and Tetsuo Ashizawa
Cells 2022, 11(9), 1567; https://doi.org/10.3390/cells11091567 - 6 May 2022
Cited by 4 | Viewed by 2363
Abstract
Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from Alu elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms [...] Read more.
Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from Alu elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases. Full article
(This article belongs to the Special Issue Noncoding Repeat Expansion Diseases: Molecular Mechanisms and Therapeutics)
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