A Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases

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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. Trinucleotide diseases are a broad family of hereditary diseases characterized genetically by an expanded DNA region consisting of a repeated three-letter code. Patients inheriting such an abnormal DNA region experience sudden disease onset at an age that inversely depends on the size of the expanded region, followed by inevitable and highly predictable suffering and death. Despite more than a decade of research, the underlying mechanism of these diseases remains an enigma. Although the genes implicated with the various trinucleotide diseases are unrelated, and the defects in these genes occur in different parts of the DNA coding for the gene, the diseases' shared characteristics suggest a common mechanism underlies their root cause. We suggest a mechanism that uniformly explains how the inherited DNA repeats genetically encode the time of onset and the rate of progression of trinucleotide diseases. It suggests the disease manifests and progresses through the further expansion of the inherited abnormally expanded DNA region. It explains the clinical data of many diseases in this family, including previously unexplained onset-related phenomena. It also predicts that a general therapy for these diseases would be a drug or procedure that successfully interferes with the ongoing expansion of the disease trinucleotide repeat.