Friday, December 6, 2019

Huntintons Disease A brief overview of current fin Essay Example For Students

Huntintons Disease A brief overview of current fin Essay dings and theories of the biochemical and molecular biological characteristics of polyQ triple repeat mutenagized coding region of the Huntingtin geneHuntington’s disease is an inherited neurodegenerative disorder. It is passed on to children from one or both parents (though two parents with Huntington’s is extraordinarily rare) in an autosomal dominant manner. This is different from autosomal recessive disorder, which requires two altered genes (one from each parent) to inherit the disorder. So if one parent has it, and passes the gene on to a child, that child will develop Huntington’s disease if they live long enough and each of that child’s’ children will have a 50% chance of inheriting the gene, and so on and so forth. If you do not have the HD gene you can’t pass it on to your children and if your mate doesn’t have it then there is no way your child will develop the disease (spontaneous cases of HD are less than 0.1%). There are no â€Å"carriers† for Huntington’s. HD is present in all areas of the world but is dominant in western Europeans and their descendants. In the United States every 1 in 10,000 people have developed HD, that’s 300,000 people with another 150,000 at risk (all of those with children have a 50% chance of passing it on). The HD gene is present at birth, but doesn’t usually develop until a persons thirties or forties. Though this is the most common time for symptoms to develop, there have been cases were symptoms developed as young as 2 and as old as 80. Symptoms begin gradually and increase over time. Huntington’s disease affects three main areas of function: motor (physical), mood (emotional), and cognition (psychological). Motor function disturbances can fall into too much movement and too little movement. Chorea, involuntary dance-like movements, can affect any part of the body. It looks like restlessness, wriggling, movement of the fingers or toes in early stages of development. These movements become larger and more sporadic over time and can involve the face, arms, legs, and trunk. It tends to lessen in the later stages. When the disease occurs in childhood (less than 10% of cases) Chorea is more severe and may coincide with rigidity or muscle stiffness and movement restriction. B oth chorea and rigidity interfere with coordination and mobility. Changes in mood are not readily noticeable as they are slow to manifest and can be interpreted as something else (i.e. HD causes depression but so does our society so this symptom often gets overlooked) Anxiety, irritability, rage, mania, and psychosis are also common symptoms. Cognition (the mental process characterized by thinking, learning, and judging) is affected early in the disease and gets worse over time. Individuals will have problems with math, memory, judgment and verbal fluency. It is very difficult for someone with HD to learn a new task, especially in the later stages of development. There currently is neither a cure nor FDA approved medical treatment for Huntington’s disease. The life expectancy is 15 – 20 years after development begins, and though Huntington’s itself doesn’t directly kill the individual, it causes so many functional breakdowns in the body that the person can no longer perform basic physical operations such as swallowing and as such a common cause of death is choking or respitory infection. Huntington disease is caused by the expansion of a polymorphic trinucleotide repeat (CAG)n located in the coding region of the Huntingtin gene. The range of these repeats in normal individuals is 9 to 37, but in HD patients it ranges from 37 to 86 and cases up 150. The human HD gene was cloned to 4p16.3 on chromosome 4 in 1993 by the HD Collaborative Research Group. The gene named IT15( important transcript 15) includes 180-200kb and consists of 67 exons. The HD mutation occurs in the first exon of this gene, which codes for a large 348kd protein named huntingtin (htt). The mutant HD gene directs the synthesis of RNA with an expanded CAG segment and consequently a protein with a lengthened stretch of consecutive glutamine residues. The HD mRNA consists of two alternatively polyadenylated species of 13.5 and 10.5 kb with the CAG repeat located near the 5end 17 codons down from the initiator AUG. The huntingtin protein has no similarity with any other reported sequences except in the low-sequence complexity polyglutamine-polyproline region (encoded by the CAG and an adjacent degenerate CCG repeat) near the NH2-terminus and a motif implicated in cellular protein transport HEAT'(a protein motif found in Huntington ,elongation factor 3 (EP3) regulatory A subunit of protein phosphatase 2A,and TORI) found in a variety of unrelated proteins. HEAT repeats are found in several cytoplasmic regulatory proteins with known roles in transport processes. The first 17 amino acids of huntingtin and the rest of the protein downstream of the polyglutamine-polyproline segment is highly conserved in evolution, the polyglutamine-polyproline segment is not, and it may be required for Huntington’s unknown function. The CAG repeat expansion is the sole mutation responsible for all inherited and sporadic cases of HD. The number of CAG repeats influences the age of onset and disease progression. Identity crisis (joy luck club EssaySo, what does all that mean (I researched this for a week and most of what I wrote still confuses me). But basically it’s this. We have a gene, Huntingtin, of whose function we don’t yet know. But we do know were it is and what it normally looks like. When it is mutagenized to extended it’s triple repeat chain of CAG it causes a change in the shape of the protein which binds to an essential enzyme for DNA function, which changes certain processes in the cell, which leads to cell apoptosis (pre-programmed, self-induced death of the cell). This happens in the brain and affects the nervous system leading to degradation of physical and mental functions and indirectly leads to death. It must be noted that over the past 10 years causes and possible cures or treatments have changed many times and this report only summarizes recent findings and understandings or theories from 1994-2001. Other interesting aspects of this topic include the first cases of genetic discrimination. Currently in the UK there is legislation allowing insurance companies to test applicants for the HD gene and if results are positive the can deny insurance to that person, or allow insurance if backed by a mortgage and $100,000 life insurance premium. While no such legislation yet exists in the U.S. we face a dilemma of our own:Huntington’s disease genomic research represents a classical ethical dilemma created by the human genome project, i.e., that of the widened gap between what we know how to diagnose and what we know how to cure. This has been referred to as a Tiresias complex. The blind seer Tiresias confronted Oedipus with the dilemma : ‘It is but sorrow to be wise when wisdom profits not’ (from Oedipus the King by Sophocles). N.S. Wexler re-stated the question as follows: â€Å"Do you want to know how and when you are going to die if you have no power to change the outcome? Should such knowledge be made freely available?†. Maybe, maybe not. But the pursuit of how and why diseases such as Huntington’s or cystic fibrosis or down syndrome or the many other genetic disorders happen will eventually lead in the knowledge of how to prevent them all together. Just give it time. Bates,G.Eberwine, J. (2001)Hunting in the Calm Before the Storm. Nature Genetics: volume 25 no.4. The Huntingtons Disease Collaborative Research Group. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes. Cell 72:971-983. Housman, D. (1995) Gain of glutamines, gain of function? Nature Genetics 10:3-4. Ashley, C.T. and Warren, S.T. Trincleotide repeat expansion and human disease. (1995) Annual Reviews of Genetics 29:703-728. Bates, G. Expanded glutamines and neurodegeneration a gain of insight. (1996) Kansas university Medical Center: Huntington Disease Clinic web page. Nasir, J. Goldberg, Y.P. and Hayden, M.R. (1996) Huntington disease: new insights into the relationship between CAG expansion and disease. Human Mitas, M. Trinucleotide repeats associated with human disease. (1997) Nucleic Gusella, J.F., Persichetti, F. and MacDonald, M.E. (1997) The genetic defect causing Huntingtons Disease: repeated in other contexts? Molecular Medicine Wellington, C.L. and Hayden, M.R. (1997) Of molecular interactions, mice and mechanisms: new insights into Huntingtons disease. Current Opinion in Neurology Chastain, P.D. and Sinden, R.R. (1998) CTG repeats associated with human genetic disease are inherently flexible. Journal of Molecular Biology 275:405-411. A brief overview of current findings and theories of the Biochemical and Molecular Biological characteristics of polyQ triple repeat mutagenized coding region of the Huntingtin geneBibliography:Attatched to paper

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