Huntington's disease: the case for genetic modifiers

Huntington's disease (HD) is a dominantly inherited disorder in which all affected individuals have precisely the same type of mutation, the expansion of a normally polymorphic CAG trinucleotide repeat in the HD gene, which lengthens a variable polyglutamine tract in the huntingtin protein [1]. Huntingtin is a large HEAT-domain protein expressed in both neuronal and peripheral tissues whose precise function is not known, though dozens of interactions with other proteins have been documented [2]. Despite widespread expression of mutant huntingtin from the time of conception, most individuals with HD are not diagnosed until mid-life, based upon the emergence of adventitious, involuntary movements that progress to a characteristic, all-consuming chorea, due to the gradual loss of neurons, most notably in the striatum and, less distinctly, in the cerebral cortex. The age at which HD can be diagnosed based upon motor symptoms is largely determined by the precise length of the expanded CAG tract, as the two are inversely correlated, with longer CAG repeats leading to earlier onset, sometimes even in the juvenile years (Figure 1) [3]. However, though it is recognized by the movement disorder produced by neuronal dysfunction and degeneration, HD has many other less specific manifestations, including psychiatric disturbances and cognitive decline, as well as non-neuronal phenotypes detected in the periphery. Indeed, the careful examination of HD mutation carriers has revealed a variety of subtle effects (such as cognitive, motor and sensory changes, as well as inflammatory markers) that are detectable many years before clinical diagnosis [4-8]. Characterization of precise genetic mouse models with the equivalent mutation introduced by knock-in techniques into Hdh, the mouse HD ortholog, indicates that molecular differences are evident even at the embryonic stem (ES) cell stage [9,10]. Thus, inheritance of the HD mutation initiates a lifelong pathogenic process (Figure 2) who