Huntington's Disease

Huntington’s disease
In 1872, George Huntington wrote the first complete description of the disease of a “hereditary chorea”. He described the principal features, which are adult onset, disease progression and eventual death, the choreiform movements in combination with the mental impairement and also its ‘inherited nature” (Kent 2004). The disease was initially known as Huntington’schorea (chorea is derived from the Greek meaning “to dance”), which is characterized by movement disorder, cognitive deteriorations and personality change. The preferred name for the disease is now Huntington’s disease (Kent 2004).
The Huntington disease gene was assigned to chromosome 4 by demonstration of close linkage to an arbitrary DNA segment that had been mapped to chromosome 4 by somaticcell hybridization.
HD was first mapped to the tip of the short arm of chromosome 4 in 1983 by James Gusella's group at Massachusetts General Hospital (Morrell 1993). The HD gene was not isolated until 1993. During most of the 10 years of work, the group had focused much of its effort on the tip of chromosome 4, near the telomere. They were led into this region, which Gusella calls "a junkyardof repetitive DNA and no genes" by their worldwide molecular genetic studies of people with HD (Morrell 1993). To narrow down their research, The Huntington's Disease Collaborative Research Group used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect (McKusick ,1986).
The discovery of an expansion of a trinucleotide(CAG) repeat region in the IT15 gene on the short arm of chromosome 4 has identified the mutational mechanism causing Huntington's disease and enables the direct diagnosis of affected subjects based on DNA analysis alone. HD is caused by an expansion in the Huntington gene, which codes for the huntingtin protein. This gene contains a repeated span of three nucleotides, C-A-G, that encode for theamino acid glutamine. Individuals with an increased number of CAG repeats in the HD gene produce a mutated version of the huntingtin protein which contains too many glutamines. Although the exact function of the huntingtin protein is not known, the mutated protein is thought to be responsible for the widespread neurodegeneration that takes place in HD (Lu Y 2011).
In the research by theHuntington’s Disease Collaborative Research Group. the genetic mutation underlying Huntington’s disease was identified as an unstable expansion of a trinucleotide (CAG) at the 5’ end of IT 15 gene on chromosome 4 (1993). This sequence may be duplicated many times in individuals, up to 26 times in the general population. The duplication of this segment is called a "trinucleotide repeat" in which thesethree nucleotides (CAG pattern) are repeated over and over again. Normal alleles at this site contain CAG repeats, but when these repeats reach 41 or more the disease is fully penetrant. Incomplete penetrance happens with 36-40 repeats, and 35 or less are not associated with the disorder. Trinucleotide CAG repeats that exceed 28 show instability on replication, with grows with increasing size ofrepeat (Walker 2007). Instability is also greater in spermatogenesis than oogenesis, in that large expansions of CAG repeats on replication happens almost exclusively in males (Walker 2007). These findings account for the occurrence of anticipation, in with the age of onset HD becomes earlier in successive generations, and the likelihood of paternal inheritance in children with juvenile onsetsymptoms. Similar, new-onsets of HD with negative family history tipically arise because of expansion of an allele in the borderline or normal range (28-35 CAG repeats), most usually on the paternal side (Walker 2007).
The most convincing evidence for a gain function in Hungtington’s disease is the structural biology of polyglutamine strands. In-vitro evidence suggest that polyglutamine will...