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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%).

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There are no “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. Both 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 5’end 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.Most HD cases show adult onset and are associated with CAG lengths of 40-50units.CAG expansions in the 35-40-unit range show very late onset or may be nonpenetrant. Individuals with more than 60 CAG repeats typically manifest juvenile onsetHD.

CAG repeats of 10-34 repeat units are associated with a normal phenotype. CAG expansions below a certain length repeats are stable at meiosis and mitosis and those above this threshold level become unstable and have the potential to undergo further expansion during successive generations. This may lead to genetic ‘anticipation’, which describes the increasing severity and decreasing age of onset in successive generations within a family. The CAG expansion in the 5′ untranslated end of the HD disease gene in paternal chromosomes at meiosis seems to account for the increased risk of juvenile HD.

Although CAG repeats may expand or contract there is a propensity towards expansion . They are less susceptible to proteolysis than contracted CAG repeats and therefore more transmissible. There is considerable evidence that the CAG expansion in HD provokes a ‘toxic gain of function’ rather than ‘loss of function’ in the mutant huntingtin (htt) protein. Patients with chromosomal deletions including the HD gene fail to manifest HD.Phenotypically normal individuals have been identified with a translocationbreakpoint disrupting the HD gene.Homozygotes are clinically identical to heterozygotes. The dominant phenotype suggests the mRNA or protein product of the disease allele has acquired a new property or is expressed inappropriately.

No missense, nonsense, frameshift or splice mutations have been found in the HD gene. HD levels of polypeptides encoded by normal and mutant allele are identical. Lately (since 1999) emphasis has been placed on elucidating the mechanisms by which the expanded CAG repeat in the htt may provoke neuronal cell degeneration in HD. Investigations have focused on identifying the biochemical substrates involved in the toxic gain of function. Intranuclear Inclusions (NII) have been found in subsets of cortical and striatal neurones in HD patients which were absent in areas of the brain unaffected by the disease.

An amino-terminal fragment of mutant huntingtin localizes to these nuclear inclusions and degenerating neurones in the HD cortex and striatum and polyglutamine length influences the extent of htt accumulation in these structures Collectively the presence of NIIs in vulnerable neurones of human disorders and their association with clinical and pathological lesions in transgenic mice have led to the theory that the deposits are toxic and therefore pathogenic. However it has never been directly shown that htt agreggations are toxic, indeed the presence of inclusions does not correlate with huntingtin -induced death. They may instead act as a cellular mechanism to protect against htt-induced cell death. Several observations support the theory that the neuronal cell death associated with HD involves apoptosis:.The nucleoli of degenerating striatal neurones in HD show characteristic morphological features associated with apoptosis.

Antiapoptotic compounds, or neurotrophic factors, protect neurones againstmutant huntingtin Blocking nuclear localization of mutant huntingtin suppressed its ability to form nuclear inclusions and induce neurodegeneration.Huntingtin demonstrates cleavage sites for apopain and caspase 3; key nuclear proteins involved in apoptosis. Apopain is involved in proteolytic cleavage of key nuclear proteins involved in apoptosis When in vitro huntingtin containing polyglutamine extended tracts was incubated with apopain it was found that the rate of htt cleavage increased dramatically with increasing polyglutamine length.

The product is a polyglutamine containing amino terminal fragment of 50-60 kD Caspase 3 is an important effecter of neural apoptosis. Huntingtin is specifically cleaved by caspase 3 and increasing polyglutamine lengths enhances this.There has been a focus on identifying proteins, which interact with huntingtin both to explain the very specific and selective neuronal loss in HD given that huntingtin is expressed in many tissues and in order to construct models that explain how proteins with expanded CAG repeats lead to neurodegeneration. Extended polyglutamine repeats induce conformational changes in the htt protein, which could expose binding sites normally inaccessible.

Several proteins have been identified which interact directly with huntingtin. Huntington-associating protein (HAP1) is a cytoplasmic protein associated withthe membrane cytoskeleton that is expressed predominantly in the brain. HAP1is expressed in many neurones that also produce neuronal nitrous oxide synthase.

Expanded CAG tracts in htt show increased binding to HAP1. This could increase nitric oxide production rendering certain cell populations more susceptible to excitotoxic damage. Glyceraldehydephosphate dehydrogenase (GAPDH), a multifunctional protein crucial to cellular glycolysis interacts with the expanded CAG containing proteins in neurodegenerative disorders including HD.GAPDH has been shown to be over expressed in cerebellar neuronal apoptosis in culture and down regulation of GAPDH is associated with decreased neuronal apoptosis. GAPDH interaction is enhanced by polyglutamine length. Both htt and GAPDH have cytoplasmic locations.

Furthermore it appears that GAPDH interacts preferentially with smaller lengths of htt compared with the full-length protein. Enhanced cleavage in cells undergoing apoptosis could generate more of the amino terminal fragment resulting in greater interaction of this truncated protein with GADPH leading to enhanced apoptosis and neurodegeneration. Human-interacting protein (HIP-2) namely human ubiquitin conjugating enzyme (hE2-25) interacts with normal htt and has known roles in protein degradation.

Huntingtin itself is ubiquinated and therefore could participate in thetoxicity of htt fragments containing polyglutamine repeats. HIP-1 is the most recently identified interactive protein. HIP-1 is a membrane-associated protein, which interacts with the cytoskeleton. It forms the strongest associations with normal htt protein and therefore could be important in the cellular functioning of huntingtin. HEAT repeats locateddownstream of the huntingtin polyglutamine tract strengthen the HIP-1-htt interaction.

HIP-1 could help in the transport of htt. There is increasing evidence that polyglutamine tracts on their own and protein fragments with extended polyglutamine tracts may be toxic to cells. It is thought that mutant htt undergoes proteolysis in the cytoplasm via interactions with cellular proteins to generate N-terminal fragments containing the toxic glutamine expansions.

These fragments would then be small enough to gain access to the nucleus where they could provoke apoptosis . A base level of caspase activity occurring in a cell under moderate stress cleaves small amounts of substrate. Huntingtin with expanded polyglutamines promotes caspase 3 cleavage which could initiate a positive feedback loop by producing a toxic amino-terminal fragment of huntingtin, adding additional stress to the cell, which would cause more caspase activation, cleavage and apoptosis.So, 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: “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 Huntington’s Disease Collaborative Research Group. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s 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 Huntington’s Disease: repeated in other contexts? Molecular Medicine Wellington, C.L. and Hayden, M.R.

(1997) Of molecular interactions, mice and mechanisms: new insights into Huntington’s 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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