Türk Nöroloji Dergisi (Feb 2005)
Molecular Biology of Huntington’s Disease
Abstract
Huntington’s Disease (HD) is the most common among nine known polyglutamine disorders. Its prevalence is estimated to be 3-7/100 000 in populations of Western European descent. HD is an autosomal dominantly inherited neurodegenerative disorder of the central nervous system, characterized by involuntary movements, impaired motor coordination, cognitive loss and various psychiatric abnormalities. The most prominent pathological finding is the selective neuron death in basal ganglia. The disease gene (IT-15), localized to chromosome 4 in 1993 and 180kb long, is composed of 67 exons. The gene product is a 348 kDa protein, called huntingtin, whose function is not known yet. The mutation causing HD is the expansion of the CAG triplet repeat in the first exon of the IT-15 gene. Huntington’s Disease Working Group has identified four repeat intervals: People who carry 26 or less CAG repeats in the IT-15 gene are healthy, alleles with 27-35 repeats may show intergenerational instability, people carrying 36-39 CAG repeats may or may not develop the disease , however 40 or more CAG repeats definitely cause HD, if people live long enough. The molecular diagnosis of HD with direct mutation analysis has been available since 1993. In this method, the CAG repeat region on the IT15 gene is PCR-amplified, and the repeat number is determined using radioactive or non-radioactive methods. Although the genetic mutation leading to HD has been identified ten years ago, the underlying molecular mechanism leading to selective neurodegeneration is not clear yet. Proteolytic cleavage and aggregate formation of the mutant protein, aberrant protein interactions and transcriptional dysregulation are possible pathogenic mechanisms. The understanding of HD pathogenesis will enlighten the way to a cure for several other neurodegenerative disorders, which are thought to share a common mechanism.
