hatAll humans have the Huntingtin gene (''HTT''), which provides the genetic code to produce the protein huntingtin (HTT). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHTT). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant, because either of a person's HTT genes being mutated causes the disease. It is not inherited according to gender, but the length of the repeated section of the gene, and hence its severity, can be influenced by the gender of the affected parent.
Genetic mutation
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The ''HTT'' gene is located on the short arm of chromosome 4
Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.
Inheritance
The probability of offspring inheriting an affected gene is 50% independent of gender, and the gene does not skip generations.
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.
Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the number of repeats present. It is rare for Huntington's disease to be caused by a new mutation, where neither parent have over 36 CAG repeats.
Individuals with both genes affected are rare, except in large consanguineous families. For some time HD was thought to be the only disease for which this did not affect the symptoms and progression of the disease, but it has since been found that it can affect the phenotype and the rate of progression. The behavior of mutated mHTT protein is not completely understood, but it is toxic to certain types of cells, particularly in the brain. Damage mainly occurs in the striatum, but as the disease progresses, other areas of the brain are also significantly affected. As the damage accumulates, symptoms associated with the functions of these brain areas appear. Planning and modulating movement are the main functions of the striatum, and difficulties with these are initial symptoms. In animals genetically modified to exhibit HD, several functions of HTT have been found. In these animals, HTT is important for embryonic development, as its absence is related to embryonic death. It also acts as an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein which protects neurons and regulates their creation during neurogenesis. HTT also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription. During the biological process of posttranslational modification of mHTT, cleavage of the protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion. Rhes was found to induce sumoylation of mHTT, which causes the protein clumps to disaggregate - studies in cell culture showed that the clumps were much less toxic than the disaggregated form. HD also causes an abnormal increase in astrocytes.
The basal ganglia - the part of the brain most prominently affected by HD - play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system
Further Reading
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