Repeat instability as the basis for human diseases and as a potential target for therapy

Castel, Arturo López; Cleary, John D.; Pearson, Christopher E.

doi:10.1038/nrm2854

Cited by 395 publications

(391 citation statements)

References 49 publications

Supporting

Mentioning

381

Contrasting

Unclassified

Order By: Relevance

“…An even greater number of similar point mutations have been described for the b-like globin genes (summarized in Giardine et al 2011). Of all such variants, a major class of mutations that is not found in the globin genes is trinucleotide expansions (Lopez Castel et al 2010). Furthermore, to date, no mutations affecting mRNAs or long noncoding RNAs have been found.…”

Section: A-thalassemia Caused By Sequence Variations In the Structuramentioning

confidence: 97%

The Molecular Basis of -Thalassemia

Higgs

2013

Cold Spring Harbor Perspectives in Medicine

125

View full text Add to dashboard Cite

The globin gene disorders including the thalassemias are among the most common human genetic diseases with more than 300,000 severely affected individuals born throughout the world every year. Because of the easy accessibility of purified, highly specialized, mature erythroid cells from peripheral blood, the hemoglobinopathies were among the first tractable human molecular diseases. From the 1970s onward, the analysis of the large repertoire of mutations underlying these conditions has elucidated many of the principles by which mutations occur and cause human genetic diseases. This work will summarize our current knowledge of the a-thalassemias, illustrating how detailed analysis of this group of diseases has contributed to our understanding of the general molecular mechanisms underlying many orphan and common diseases.

show abstract

Section: A-thalassemia Caused By Sequence Variations In the Structuramentioning

confidence: 97%

The Molecular Basis of -Thalassemia

Higgs

2013

Cold Spring Harbor Perspectives in Medicine

125

View full text Add to dashboard Cite

show abstract

“…Genetic anticipation in these diseases occurs because the repeats are meiotically unstable and tend to expand over successive generations; most also show tissue‐specific somatic instability10 (see Table 1). In HD, somatic instability is expansion‐biased and age‐ dependent, with larger tracts more susceptible to expansion 11, 12.…”

mentioning

confidence: 99%

“…Somatic instability has been linked to disease onset and progression in both human14 and mouse HD studies,15 and decreasing somatic expansion in HD model mice delays phenotype progression 16. Many of the principles of somatic instability in HD extend to SCAs 1, 10. Somatic instability12, 17, 18 has been attributed to the actions of DNA repair proteins, and as well as the individually associated variants, the GeM‐HD GWAS found significant association between age at motor onset and several DNA repair pathways 6.…”

mentioning

confidence: 99%

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

198

186

View full text Add to dashboard Cite

ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

show abstract

“…In the germ line, expansions lead to earlier disease onset and increased severity in affected individuals (40), while expansions in specific types of neuron may exacerbate the disease phenotype (13,40,49). Treatments designed to prevent repeat expansion or to promote repeat contraction would be welcome, but no such treatments exist, and their development will depend on a better understanding of the mechanisms responsible for repeat instability (34).…”

mentioning

confidence: 99%

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

Expanded trinucleotide repeats are responsible for a number of neurodegenerative diseases, such as Huntington disease and myotonic dystrophy type 1. The mechanisms that underlie repeat instability in the germ line and in the somatic tissues of human patients are undefined. Using a selection assay based on contraction of CAG repeat tracts in human cells, we screened the Prestwick chemical library in a moderately highthroughput assay and identified 18 novel inducers of repeat contraction. A subset of these compounds targeted pathways involved in the management of DNA supercoiling associated with transcription. Further analyses using both small molecule inhibitors and small interfering RNA (siRNA)-mediated knockdowns demonstrated the involvement of topoisomerase 1 (TOP1), tyrosyl-DNA phosphodiesterase 1 (TDP1), and single-strand break repair (SSBR) in modulating transcription-dependent CAG repeat contractions. The TOP1-TDP1-SSBR pathway normally functions to suppress repeat instability, since interfering with it stimulated repeat contractions. We further showed that the increase in repeat contractions when the TOP1-TDP1-SSBR pathway is compromised arises via transcription-coupled nucleotide excision repair, a previously identified contributor to transcription-induced repeat instability. These studies broaden the scope of pathways involved in transcription-induced CAG repeat instability and begin to define their interrelationships.

show abstract

Repeat instability as the basis for human diseases and as a potential target for therapy

Cited by 395 publications

References 49 publications

The Molecular Basis of -Thalassemia

The Molecular Basis of -Thalassemia

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Contact Info

Product

Resources

About