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Molecular mechanisms underlying nucleotide repeat expansion disorders
Open accessAbstract
The human genome contains over one million short tandem repeats. Expansion of a subset of these repeat tracts underlies over fifty human disorders, including common genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72), polyglutamine-associated ataxias and Huntington disease, myotonic dystrophy, and intellectual disability disorders such as Fragile X syndrome. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.
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“Furthermore, ALS is characterized by aberrant RNA processing and nucleocytoplasmic transport defects, which are often linked to mutations in C9orf72 and other RNA-binding proteins.193”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [193]
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Metadata
- Authors
- Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K.
- Affiliations
- University of Michigan (US)
- University of Florida (US)
- Corresponding author
- Todd, Peter K.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2021-06-17
- Volume
- 22
- Issue
- 9
- Pages
- 589-607
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- PMC
- PMC9612635
- OpenAlex
- W3170696603
- Cited by
- 363
- References
- 286
- Citations by year
- 2026: 71 · 2025: 77 · 2024: 92 · 2023: 66 · 2022: 48 · 2021: 9
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-07-06)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX004842)
- National Institute on Aging (R01AG058636)
- National Institute of Neurological Disorders and Stroke (R01NS112291, R01NS086810, R01NS114253, R01NS099280)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD104463)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- microsatellite markers, C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, myotonic dystrophy, fragile X syndrome, transcriptional repression, repeat-associated non-AUG translation, age of onset, tissue specificity, therapeutic target
- MeSH terms
- R-Loop Structures, Animals, Humans, Mutation, Organ Specificity, RNA, Protein Biosynthesis, RNA-Binding Proteins, Neurodegenerative Diseases, Gene Silencing, DNA Repeat Expansion, Genomic Instability
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