Repeat Instability, DNA Mismatch Repair and Potential for Drug Development in Repeat Expansion Disorders
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".
Deadline for manuscript submissions: 20 March 2025 | Viewed by 361
Special Issue Editor
Interests: processes that modify and generate genetic variation (within individuals and populations as well as between populations); phenotypic consequences of genetic variation; repeat expansion disorders with a focus on Huntington disease
Special Issue Information
Dear Colleagues,
The expansion of certain simple sequence repeats is known to be associated with a growing number of inherited human disorders, primarily neurological ones, including fragile X syndrome, myotonic dystrophy types 1 and 2, Huntington disease, multiple spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, Friedreich ataxia, amyotrophic lateral sclerosis and Fuchs corneal dystrophy. The disease-associated repeats are genetically unstable. Germline repeat instability frequently leads to an increase in repeat length from one generation to the next, and somatic repeat instability leads to an increase in repeat length in specific cell types throughout the lifetime of the individual. In general, the more repeats an individual inherits, the more severe the symptoms and the earlier the age at onset. Besides the length of the inherited disease-causing repeat, the rate at which somatic repeat expansions accumulate in particular cell types is a likely determinant of disease progression and severity. Several DNA mismatch repair proteins have been linked to disease severity and somatic expansion of the disease-causing repeat in multiple repeat expansion disorders. This suggests the existence of a pathogenic DNA mismatch mechanism, common to multiple repeat expansion disorders, operating through its direct effect on the somatic expansion of the disease-causing repeat. This shared somatic repeat expansion mechanism offers a therapeutic opportunity for strategies aiming at slowing down the accumulation of somatic expansions, as some could be applicable to multiple disorders.
This Special Issue aims to highlight recent advances in the field, emphasising commonalities in repeat instability across various expansion disorders. By fostering a deeper understanding of the shared mechanisms, the issue aims to inspire innovative solutions for effective therapeutic interventions for repeat expansion disorders.
This Special Issue invites original studies and review articles covering, but not restricted to, the following themes:
- Accurate genotyping of repeat expansions;
- Precise measurement of repeat instability;
- Identification and validation of new targets;
- Effective drug delivery methods;
- Establishment of target engagement biomarkers.
Dr. Marc Ciosi
Guest Editor
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Keywords
- repeat instability
- inherited human disorders
- drug delivery
- DNA mismatch repair
- biomarkers
- unstable repeat expansions
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