Huntington's Disease Summary

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Huntington’s disease (HD) is a late-onset, usually between 35 and 50 years old, neurodegenerative disorder prevalent in 3-7 per 100,000 people of European ancestry1. The disease, inherited in an autosomal dominant pattern2, is characterized by motor disturbance, intellectual decline, and psychiatric manifestations3. The disease is difficult to detect at an early stage of an individual’s life since its symptoms appear in the third to fifth decade of life. To better understand the disease, investigations were done to identify the gene that is linked with the disease. Some of the common approaches to do this was linkage analysis and positional cloning often involving the use of polymorphic DNA markers to identify the best candidate gene that can …show more content…
in 1983. Taking advantage of the recombinant DNA technology, they used restriction fragment length polymorphisms (RFLPs) as DNA markers to determine linkage of the disease gene in large multigenerational families. The DNA of the affected individuals from two families of American and Venezuelan descent was analyzed using DNA probes. The latter, which were free of repetitive sequences, can detect RFLPs which were present in the regions of the genome. The researchers constructed a human genetic linkage map, thus, they were able to localize the genes that can give a suggestion of linkage to the disease. Their experiment resulted to a G8 marker being linked to the disease gene. Using a Southern blot analysis of human/mouse somatic cell hybrids, they mapped the G8 marker to a human chromosome. The mapping revealed that the marker was found to be associated with chromosome 4. A linkage analysis of the G8 marker on chromosome 4 and the HD locus was conducted. For a linkage between two loci to exist, a lod score of greater than 3 should be established. In their study, the linkage analysis revealed a total lod score of 8.53 at θ = 0.00. Therefore, there was a strong evidence that the two loci are closely linked and that there was no recombination between the loci suggesting that these loci are inherited together as a …show more content…
In 2001, Auerbach et al. studied the effect of mutation in HD when the protein huntingtin was limiting. Generally, the study showed that there were lethal neurological effects observed in the heterozygous Hdh knock-in mice with low levels of mutant huntingtin containing 111 glutamines (Q111) and 20 glutamines (Q20). They also found out that there were brain deficits and abnormal development with the mice having low level of Q20 huntingtin in the absence of Q111. Together, the study showed a novel disease caused by low levels of mutant huntingtin distinct from striatal pathology. The reduced expression of huntingtin influences the central nervous system to the toxic effects of very low mutant protein. In another study conducted by Dyer et al. on the same year, they have demonstrated that the mutant protein huntingtin’ resistance to proteolytic activities can cause toxicity in the cell due to the aggregation of fragments containing expanded polyglutamine repeats and the sequestration of important cellular targets including normal HD. The effect of huntingtin on cellular toxicity was further investigated by Nucifora et al. Their experiments revealed that cellular toxicity may also be caused by the interaction between the huntingtin with other proteins containing a short glutamine repeats. They have shown that huntingtin

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