ArticlePLoS computational biology2007
A universal mechanism ties genotype to phenotype in trinucleotide diseases.
Article in PLoS computational biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 84 citations in OpenAlex.
- Somatic CRISPR editing ofbioRxiv : the preprint server for biology · 2026Article
- MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism.American journal of human genetics · 2026Article
- Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding.Nature communications · 2025Article
- Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.Brain : a journal of neurology · 2025Article
- Article
- Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.Nature medicine · 2025Observational
- Review
- Article
- Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.Current neurology and neuroscience reports · 2025Review
- Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions.Human molecular genetics · 2024Article
- Neuroinflammatory Proteins in Huntington's Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications.International journal of molecular sciences · 2024Review
- Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease.Human genetics · 2024Article
- Comment on: "Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype" by Ruiz de Sabando et al.European journal of human genetics : EJHG · 2024Article
- Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype.European journal of human genetics : EJHG · 2024Article
- Review
- Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease.eLife · 2024Article
- CAG repeat mosaicism is gene specific in spinocerebellar ataxias.American journal of human genetics · 2024Article
- Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat.Nature communications · 2024Article
- Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.Nature genetics · 2024Article
- Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group.Journal of Huntington's disease · 2024Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype-phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.
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