A universal mechanism ties genotype to phenotype in trinucleotide diseases

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.

Figure 1. A Universal Mechanism for Trinucleotide Diseases

(A) The patient inherits one gene (or two genes in recessive disease) that harbours a trinucleotide repeat that exceeds disease-specific threshold (green line, I = 38 repeats in this example). (B) A disease-specific group of cells that determines the disease onset and progression is initially clustered around the inherited value. (C) During the lifetime of the patient, the number of repeats in these cells increases stochastically, (D) some crossing a pathological threshold (red line, 150 in this example) while the patient is still considered healthy. (E) Disease commences when in a critical portion of these cells (C = 20% in this example) the number of repeats crosses the pathological threshold. (F) The disease progresses toward death as more cells cross the target threshold. (G) The rate of allele expansion E at any given time is a linearly increasing function of the number of repeats above the initial threshold. (H) Equations for the mean and standard deviation of allele size as a function of the patient's age t, inherited number of repeats L₀, and the mechanism parameters (see Materials and Methods and Text S1). (I) The mechanism predicts an exponentially decreasing onset curve similar to curves obtained from clinical data for trinucleotide diseases.

Figure 2. Exponential Onset Curve

(A) The mechanism, with parameters fitted to the clinical data [8] of HD, predicts pathological threshold around 115 CAG repeats. (B) The somatic expansion of repeats as a function of age of patients with HD with various inherited allele size. Onset occurs when enough cells (critical portion of 20%) cross the pathological threshold (red line). The slower expansion of shorter alleles (40–50 repeats) accounts for a larger difference in the age of onset (26 y) in contrast to longer alleles (60–70 accounts for only 7 y). A single-repeat (39–40) difference in short alleles close to the initial threshold (green line) may reduce several years from onset age compared to a single repeat difference in longer alleles (49–50).

Figure 3. Computer Simulations of the Mechanism in Patients with Two Disease Alleles

Simulation results for patients of (A) dominant and (B) recessive diseases with various combinations of two inherited alleles. The age of onset as a function of short/long allele size and regression line are presented. In a dominant disease (A), only the longer allele size is in strong anticorrelation (r = −0.99) with age of onset, while in a recessive disease only the shorter allele is in strong anticorrelation (r = −0.99), consistently with corresponding data for dominant polyglutamine diseases and the recessive disease FRDA [32].

Figure 4. Simulation of Two Hypothetical Patients with HD

The variability of repeat-size distribution is zero at birth and increases during the patient's lifetime as a result of the independent stochastic expansion process. At the time of onset (20% of the cells exceed the pathological threshold) a wide distribution in the CAG₄₀ patient with late onset (A) accounts for slower progression (only 35% of cells exceed pathological threshold after 4 y) while a narrow distribution in the CAG₇₀ patient with juvenile onset accounts for faster progression (85% after 4 y).

Figure 5. Homozygote versus Heterozygote Patients

(A–C) Simulation results show the long allele distribution at onset for heterozygote patients (A) with onset at 60 y and homozygote patients (B) with onset at 56 y, both with 40 inherited repeats. The homozygote patients show more narrow distribution, which is closer to the pathological threshold, which leads to a faster disease progression. (C) The difference in age of onset is rather small (homozygote ∼6% earlier) and therefore is undetectable considering other variability factors; however, the difference in progression is significant (homozygote ∼30% faster).