Genetic criteria for Huntington's disease pathogenesis.
Genetic analysis aims to identify the variations in DNA sequence whose functional consequences produce heritable variations in phenotype. In one of the first successes of unbiased molecular genetic analysis in human disease, the Huntington's disease (HD) gene was mapped and cloned without any prior knowledge of the nature of its protein product or of the molecular defect that underlies the characteristic phenotype of the disorder. However, while the cloning of HD and recognition of its trinucleotide repeat expansion spawned a plethora of approaches to investigating HD through its distinctive neuropathology, the role for genetic strategies in HD research did not end there. The use of genetic analysis has remained a critical tool for defining the characteristics of the mechanism that triggers the pathogenic process, permitting the investigation of early events that occur long before traditionally recognized pathology. Delineation of these events can reveal molecular targets for development of therapies that prevent onset of HD. Most recently, an extension of genetic analysis to the identification of non-linked genetic variations that alter the course of HD pathogenesis has offered the promise of identifying modifier genes to reveal biological pathways active throughout the disease process and to provide valid targets for pharmacological intervention. Thus, unbiased genetic strategies have not only provided a crucial entrée into molecular investigation of HD via a root cause that was previously unsuspected, they also represent a continuing route to accelerate the ultimate goal of developing an effective treatment for HD.
Gusella
James F
JF
Center for Human Genetic Research, Massachusetts General Hospital, CPZN-5830, Boston, MA 02114, USA. gusella@helix.mgh.harvard.edu
Macdonald
Marcy
M
D000818:Animals; D005821:Genetic Techniques; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*