We searched PubMed for papers published from Jan 1, 2012, to Sept 30, 2016, using combinations of the terms “huntingt*”, “spinocerebellar ataxia”, “trinucleotide repeat”, “triplet repeat”, “repeat”, or “repeat disease”, and “DNA integrity”, “DNA repair”, “genome integrity”, or “genome repair”. Our search was limited to publications that included search terms in the title, abstract, or both. We identified further relevant papers by searching the reference lists of retrieved papers and through
Rapid ReviewDNA repair in the trinucleotide repeat disorders
Introduction
Trinucleotide repeat disorders—inherited diseases caused by unstable repeated DNA sequences—were first characterised in the 1990s and are individually rare.1 Fragile X syndrome is the most common, with a prevalence of about one per 4000 boys. Myotonic dystrophy and Huntington's disease affect around one per 10 000 people, and most spinocerebellar ataxias affect around one per 100 000 people, although the prevalence of Huntington's disease and the spinocerebellar ataxias varies widely across geographical regions. Only a few cases have been identified for other such disorders. Together, however, trinucleotide repeat disorders represent a substantial source of morbidity. Most are life-shortening and have debilitating symptoms, and no disease-modifying treatments are available. Although the mutational mechanisms are similar, the repeated DNA sequences occur in different genomic contexts, and even in the polyglutamine diseases, where the repeated codon is translated to glutamine, the proteins are functionally unrelated. The nature and expression pattern of the repeat-containing proteins probably leads to the clinical differences between these diseases,1 but the substantial phenotypic variation seen within each disease remains only partly explained. This variability can be exploited to gain insights into disease mechanisms though genetics.2
The trinucleotide repeat disorders fall into two main categories: those in which the repeated sequence is translated into a protein product and those in which the repeat lies outside the coding sequence (table 1), but the non-coding disease-associated repeat sequences are usually longer than the coding sequences. All the trinucleotide repeat disorders are associated with genetic anticipation—earlier onset of disease in successive generations of families—caused by germline expansion of the repeat.16 Repeat expansion occurs in dividing and non-dividing cells, and is tissue specific, cell specific, and disease specific.1 Expansion of the repeat is ameliorated if the repeated sequence is interrupted by other codons.
Although associations between repeats and specific loci have been known since the 1990s, the mechanistic cascade from repeat to clinical phenotype remains unclear in trinucleotide repeat disorders, which has hindered the development of new treatments. Some pathogenic mechanisms are common to multiple diseases. For instance, a repeat that prevents gene expression is seen in fragile X syndrome and Friedreich's ataxia.17 Pathogenic RNA foci in myotonic dystrophy and myotonic dystrophy-like 2 give rise to characteristic splicing deficits,18 and have been noted in other trinucleotide repeat disorders, such as myotonic dystrophy 1 and 2.19 Repeat-associated non-ATG translation, which was first identified in myotonic dystrophy and spinocerebellar ataxia 8,20 has since been found in Huntington's disease,21 frontotemporal dementia and amyotrophic lateral sclerosis (which are caused by the C9ORF72 hexanucleotide repeat), and other trinucleotide repeat disorders.22 In frontotemporal dementia and amyotrophic lateral sclerosis, the C9ORF72 disease-associated repeat dipeptides are neurotoxic,23 although whether such dipeptides have any pathogenic role in trinucleotide repeat disorders is unknown.
Similar mechanisms might be seen in the polyglutamine (CAG repeat) diseases;22 however, the proteins that contain expanded polyglutamine tracts aggregate and form characteristic insoluble protein inclusions in neural and other cells in these disorders. Such insoluble inclusions are also widely seen in other neurodegenerative disorders,24 which has led to the hypothesis that they or their soluble oligomers are pathogenic. So far, the notion that preventing aggregation can prevent disease in human beings has not been proven.25 Nevertheless, some findings hint at this possibility. For example, in trials of aducanumab, an antibody that binds and reduces deposition of amyloid β, cognitive benefits were recorded in mouse models and in clinical studies of people early in the course of Alzheimer's disease.26 Ataxin 1 (ATXN1) oligomers drive the degenerative effects in spinocerebellar ataxia 1 and induce local spread of pathology.27 These effects were partly inhibited with immunotherapy.28 The biological consequences of expanded polyglutamine have been extensively studied and a wide range of potentially harmful outcomes detected,29, 30 but which of these are important in the manifestation of disease remains unclear. Genetic evidence indicates that the DNA damage response and DNA repair affect the clinical presentation of Huntington's disease and multiple spinocerebellar ataxias,31, 32, 33 which suggests that there are common modifiers that act on the mutated repeat itself. Together with evidence implicating these processes in trinucleotide repeat disorder biology, these findings shed light on specific mechanisms and highlight new targets for therapeutic intervention.
Section snippets
The DNA damage response and neurological disease
The DNA damage response (table 2) can be both harmful and protective in people with neurological diseases. Mutations in genes involved in the DNA damage response were first noted to cause neurological disease in ataxia-telangiectasia, a rare recessive childhood neurodegenerative disease. Mutations in the ataxia-telangiectasia mutant serine/threonine kinase gene (ATM) cause ataxia-telangiectasia. This gene controls cell-cycle arrest after DNA double-strand breaks, often leading to apoptosis and,
Genetic modifiers in the trinucleotide repeat disorders
One way of overcoming the difficulties of interpreting the cell biology findings is to return to the study of people carrying repeat expansions. In natural experiments,2 where conditions are not controlled by the researchers, it is possible to search for genetic loci that modify disease in a beneficial or deleterious way, and to reveal the biology that is likely to be relevant to disease manifestation. For instance, if genetic variation affects the timing of disease onset or the progression or
DNA repeat expansions and the DNA damage response
Repeat expansions in DNA are affected directly by activities of the DNA damage response (table 2).8 The repeats undergo expansion on transmission through the germline, in dividing and terminally differentiated somatic cells, and the repeat size increases with age.8 Strand breakage in the repeat is repaired, and it is at this point the repeat sequences are thought to expand.64, 68 The length of the repeat expansion in Huntington's disease correlates positively with the propensity for further
Conclusions and future directions
Showing that genetic modifiers exist in Mendelian trinucleotide repeat disorders demonstrates that finding genetic modifiers in rare genetic diseases is possible, and highlights areas of biology that modulate disease in people, such as specific aspects of the DNA damage response: mismatch repair, base-excision repair, and the Fanconi anaemia pathway. The findings raise two important questions. The first is whether genetic association with DNA repair processes occurs across all the trinucleotide
Search strategy and selection criteria
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