Huntington's disease: the case for genetic modifiers

Abstract

For almost three decades, Huntington's disease has been a prototype for the application of genetic strategies to human disease. HD, the Huntington's disease gene, was the first autosomal defect mapped using only DNA markers, a finding in 1983 that helped to spur similar studies in many other disorders and contributed to the concept of the human genome project. The search for the genetic defect itself pioneered many mapping and gene-finding technologies, and culminated in the identification of the HD gene, its mutation and its novel protein product in 1993. Since that time, extensive investigations into the pathogenic mechanism have utilized the knowledge of the disease gene and its defect but, with notable exceptions, have rarely relied for guidance on the genetic findings in human patients to interpret the relevance of findings in non-human model systems. However, the human patient still has much to teach us through a detailed analysis of genotype and phenotype. Such studies have implicated the existence of genetic modifiers - genes whose natural polymorphic variation contributes to altering the development of Huntington's disease symptoms. The search for these modifiers, much as the search for the HD gene did in the past, offers to open new entrées into the process of Huntington's disease pathogenesis by unlocking the biochemical changes that occur many years before diagnosis, and thereby providing validated target proteins and pathways for development of rational therapeutic interventions.

Figure 1

Inverse correlation of age at neurologic onset and HD CAG repeat length. The plot shows data points from 1,200 HD subjects of known age at neurologic onset. For each individual, the measured CAG repeat length in blood DNA (x-axis) is plotted against age at neurologic onset (y-axis). The line represents the best-fit simple logarithmic regression to the data. The CAG repeat length accounts for approximately 67% of the overall variation in age at neurologic onset, and the remaining variation shows a heritability of approximately 0.56.

Figure 2

Huntington's disease is a lifelong disorder. The schematic diagram depicts the lifelines of a typical normal individual and a typical individual carrying the HD mutation. The darkening arrows illustrate the changes that occur during the lifetime of each individual as they proceed from conception to death. The use of different colors denotes that the HD subject is never the same as the normal individual, differing even shortly after conception in the expression of mutant huntingtin and its biochemical consequences. The differences lead over time to a variety of phenotypes whose order of appearance and interdependence are not well defined, particularly prior to clinical diagnosis, which is currently based upon the characteristic movement disorder. Death ensues after an inexorable clinical decline, usually approximately 15 years after the appearance of diagnostic movements. Genetic modifiers (blue upward arrows), which could theoretically act at any stage and on any phenotype, are currently being sought for the phenotype of diagnostic motor onset, as the residual variation in this phenotype after accounting for the effect of the HD CAG repeat is highly heritable.