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Wilsons Disease Research Paper

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Wilson’s disease is a condition which causes neurological symptoms such as tremors, stiffness of muscles, difficulty of speech, and psychosis, as well as physical symptoms such as oedema, jaundice, and nausea. It has been identified as an autosomal recessive genetic disorder which prevents normal excretion of copper from the body (Weiss KH, 1999).

It was first recognised as a disease in 1912 by British neurologist Samuel Alexander Kinnier Wilson, who drew on the earlier, independent works of Carl Westphal, William Gowers, and Adolph Strümpell, to identify the characteristic changes of the brain and liver (Wilson SAK, 1912). John N. Cumings subsequently identified the role of copper accumulation in the disease, as well as the haemolytic effect …show more content…

The first hints of a genetic basis for Wilson’s disease were identified in 1953, when A. G. Bearn conducted a study of sixteen families, analysed the occurrence of Wilson’s disease by constructing pedigrees, and collated his data with the earlier work of others to substantiate the idea that Wilson’s disease is inherited recessively (Bearn AG, 1953).

The next major component of a genetic case for Wilson’s disease came about in the mid-80’s, when two researchers independently mapped the gene associated with Wilson’s disease to an area on chromosome 13 (Friedman M, 1985; Bowcock AM, 1987). This was achieved by analysing the pedigree of a large family with multiple individuals affected by Wilson’s disease and comparing autosomal markers such as erythrocyte enzymes, erythrocyte proteins, and plasma proteins to the occurrence of Wilson’s disease. Of the fifteen markers tested, Esterase D (its locus on the q arm of chromosome 13 confirmed by somatic cell hybridzation) was the only marker to exhibit any evidence of linkage (Chen et al, 1975; Friedman M, 1985). LOD scores were calculated, suggesting a recombination fraction of 6 centiMorgans (Friedman M, 1985). This meant predictive testing for Wilson disease disease could now be performed, even though a specific gene had not yet been identified (Farrer LA, …show more content…

Researchers used a translocation breakpoint on the X chromosome common to females with the disease to identify a region between near the pGK-1 locus where they believed the gene associated with Menkes to be located (Mercer et al, 1993). Polymerase chain reaction (PCR) was first used to screen a large YAC library for an appropriate YAC using a primer targeted to one side the pGK-locus. 2 YACs were found which spanned the first translocation breakpoint. Following that, fluorescent in-situ hybridisation was used to identify which of those YACs possessed DNA which spanned both the translocation breakpoint in question, as well as the sequential one. Internal and flanking probes were constructed from clones of the YAC in question and were used to make a restriction map (Mercer et al, 1993). A partial digest of EcoRI and subsequent Southern hybridisation revealed a DNA fragment which crossed the breakpoint, and proved to be the location of the gene responsible for Menkes. By matching known regions of DNA to the fragments of the digested clone via Southern and Northern blot analysis, a gel band was identified that was homologous to all Menkes patients, comfirming its identity. In sequencing this region, researchers observed that the gene (ATP7A) shared a highly conserved “heavy metal

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