Genetic Indicators And Variable Relationships In Huntington’s Disease

Abstract
Huntington’s disease or HD is a genetic disorder that affects the central nervous system and it has symptoms that usually occur in adults within their fourth and third phases of their lives, although these symptoms and signs can manifest themselves in individuals older or younger than these stages. This paper will look at the disease and its causes and discuss a number of factors related to the disorder like genetic indicators and variable relationships that occur in Huntington’s disease. To achieve this, the essay will talk of the name, the size and the locus of the gene in addition to the wild type allele’s mRNA exons’ size. Other than this, the article will also discuss the size, name, number of amino acid alterations and number of the wild type amino acids of the nucleotide molecule or protein affected by the disorder in its mutant form. Further, the roles of the wild type, normal and gene product will be illustrated.

Introduction
Huntington disease is a progressive disorder of the brain that leads to onset of uncontrolled movements, loss of ability to think and emotional problems. Huntington disease affecting adults is one of the key forms of the disorder and it in most cases appears when an individuals in his forties or thirties. Some of the early symptoms and signs of the disorder at times include depression, irritability, small involuntary movements, trouble learning new ideas and information, poor coordination and poor capacity to make decisions. Most individuals suffering from the disorder develop involuntary twitching and jerking movements referred to as chorea, as the disorder develops and progresses, these movements become more prominent and consisted (Nussbaum, McInnes, Willard, Thompson & Thompson, 2007).

As it follows, individuals with the disorder might have problems walking, swallowing and even speaking. They also experience alterations in their personalities and a decrease in their reasoning and thinking abilities. People with the adult- onset form usually live for more than 15 years after the onset of symptoms and signs. Another form of the disorder is observed in adolescents and children. It also involves challenges with movement and emotional and mental changes. Furthermore, additional signs of this form usually include clumsiness, slow movements, constant falling, slurred speech, rigidity and drooling. Performance in academics usually decreases as reasoning and thinking abilities diminish (Nussbaum, McInnes, Willard, Thompson & Thompson, 2007).

Huntington’s disease is a generative neurological disease that results from irregular expansions of the CAG or glutamine repeats. The numbers of CAG repeats are inversely proportional to the disorder on- set. The disorder is an autosomal dominant disease, and, therefore, it does not skip generations in a family tree. The gene affected by the disorder is located on chromosome 4 and it is called the HTT or huntingtin gene found on the p arm 16.3. The gene codes for the Htt protein product. The normal or the wild type of the huntingtin gene has CAG nucleotide repeats that are highly polymorphic in the first exon towards the five prime end. The CAG nucleotide repeats codes for the glutamine protein. The disorder occurs because of the extension of the repeats of CAG in this particular exon. Distinct lengths of this area lead to different times of on- set of the disorder, the wild type gen has about 10 to 26 repeats, 28 to 35 unaffected intermediates, 36 to 40 decreased penetrance, and the mutant alleles have less than 40 affected intermediates. The following table summarizes the mutation in Huntington disease (Pritchard & Korf, 2007).

 

Phenotype No. Of CAG repeats
Normal <26
Normal 27- 35
Mild Huntington disorder 36- 39
Adult on- set >40
Juvenile on- set >55

Around three percent of the total patients are thought to have got the disorder from a de nova or new mutation as compared to the more than 97 percent of the patients who inherit the disorder from a parent. A possible cause of the expansion of the repeated CAG sequence in the disorder is thought to be the slippage of the DNA- polymerase (Pritchard & Korf, 2007).

Everyone has two copies of the HTT or the Huntingtin gene which codes leading to the production of the protein Htt or Huntingtin. The gene is also referred to as IT15 and HD, which means interesting transcript 15. Part of the gene HTT is a repeated sequence called the trinucleotide repeat. This repeat varies in length between different people and may change in size and length between different generations. When the length of this repeated segment reaches a certain level, it produces a form of protein that is altered called the mHTT protein or the mutant Huntingtin protein. The distinct roles of these proteins are the main causes of pathological alterations which also lead to the signs and symptoms of the Huntington’s disease. The Huntington’s disorder mutation is almost fully penetrant and it is genetically dominant. This means that the mutation of either of the HTT genes of an individual can lead to the on- set of the disorder. The disorder is not inherited from parents according to sex, but the length or size of the repeated segment of the HTT gene, and, therefore, the severity of this repeated sequence in causing the disorder can be influenced by the parent’s sex, carrying the HTT gene (Walker, 2007).

The HTT gene has a sequence of 3 DNA bases namely cytosine, C,  adenine, A, and guanine, G, repeated several times to produce a nucleotide with a sequence like …CAGCAGCAGCAG… and so forth, and it is usually referred to as a trinucleotide repeat. CAG is also the genetic code that codes for the synthesis of the glutamine amino acid (Walker, 2007). As it follows, a series of them leads to the synthesis of a glutamine chain called a polyglutamine tract or a polyQ tract. The polyQ region is the name given to the repeated area of the HTT gene. In most case, individuals have less than 36 repeated glutamines in the polyQ region which leads to the synthesis of Huntingtin, a cytoplasmic protein. However, if it comes about that one has a sequence of 36 or more of glutamines then a protein that has distinct characteristics results. The mutant Htt is the altered form of the Htt protein and it increase the rate of decay of certain forms of neurons. Regions of the brain contain differing reliance on and amount of these neuron types, and are, therefore, accordingly affected. In most cases, the number of repeats of the CAG trinucleotide is related to the amount of the process affected, and accounts for not less than 60 percent of the differences in age of the onset signs and symptoms. The rest of the observed variation is related to the environment and other types of genes that alter the mechanism of the Huntington’s disorder (Walker, 2007).

The normal gene, the gene product, as well as, the wild type has different essential roles in the disease. For instance, the polyQ- expanded gene is toxic and dangerous to neurons, especially the MSNs or the medium spiny neurons found in the striatum. Just the same way, wild type huntingtin has essential- indeed indispensible- protective roles. Any effective therapy has to preserve the wild- type huntingtin expression, while silencing the mutated allele. A number of studies have found that silencing specific mutant species as opposed to depleting wild- type huntingtin actually lowered the activation of caspase-3 and protected Huntington’s disease cells under conditions of stress. Such findings have a number of therapeutic implications not only for Huntington’s disease, but also for other disorders resulting from autosomal dominant mutations. The results also show the essential role of the wild- type huntingtin gene (Abdelgany, Wood & Beeson, 2003).

The resulting mutated protein also has significant roles in the development of the disease including cellular changes and macroscopic changes. There a number of ways through which the toxic roles of mHTT may produce and manifest the Huntington disease. During the posttranslational modification biological process of mHtt, cleavage of the protein can result to shorter fragments made of parts of the polyglutamine expansion. The glutamine has a polar nature, which results interactions with several other nucleotides or proteins when it is present in large amounts in Htt proteins. Therefore, the Htt molecule strands forms hydrogen bonds with each other, creating an aggregate of proteins rather than folding into proteins that are functional. With time, these aggregates increase ultimately interfering with the functions of neurons as these fragments can then coalesce and misfold in a process referred to as protein aggregation forming inclusion bodies in cells. These inclusions in turn cause indirect interference. With time fewer neurons are present for release in signaling other neurons as the inclusions increase (Rubinsztein & Carmichael, 2003).

Conclusion
Huntington’s disease is a serious disorder that affects the neurons of an individual’s, and hence their ability to reason, to think, to move, to speak and coordinate. There have been numerous studies on the disorder but a treatment has not yet been found.

References
Abdelgany, A., Wood, M. & Beeson, D. (2003). Allele- specific silencing of a pathogenic mutant     acetylcholine receptor subunit by RNA interference. Hum Mol Genet. 12, 2637- 2644.
Nussbaum, L., McInnes, R., Willard, H. Thompson & Thompson. (2007). Genetics in Medicine.     New York: Saunders/Elsevier.
Pritchard, J. & Korf, R. (2007). Medical Genetics at a Glance. New York: Blackwell publishing.
Rubinsztein, D. & Carmichael, J. (2003). Huntington’s disease: Molecular basis of     neurodegeneration. Expert Rev Mol Med 5 (20): 1–21.
Walker, O. (2007). Huntington’s disease. Lancet 369 (9557): 218–28.