Huntingtin (Htt) is a gene found on chromosome 4.
In Huntington's disease, people have at least one mutated copy of the gene.
This mutation has been found to be a gain of function mutation. This means that the effects of the disease are not caused by a lack of the working gene but instead the mutated gene is toxic to the cell. Individuals who have a disease called Wolf-Hirschman are lacking a copy of chromosome 4 which includes lacking the Htt gene. However they don’t have the symptoms of Huntington's disease as their remaining copy is not mutated and sufficient for normal function.
Htt is important for many normal body processes. It is not fully understood what the complete role of the gene is however it is involved in the following;
- · Embryonic development – mice KO studies show mice without Htt die before birth.
- · Vesicular transport and synaptic transmission of neurones in the brain.
- · Apoptosis- normally Htt prevents apoptosis however the mutated form can cause apoptosis.
- · BDNF transcription – This is a protein which is involved in the development of neurones and protection of neurones.
The main areas where Huntington's disease has its affect are in the Basal Ganglia and Substantia Nigra; two areas of the brain that are involved in the control of movement. Huntington's disease causes progressive damage of neurons and cells in these regions which causes the slow or jerky movement’s characteristic of Huntington's disease.
The Htt gene contains a sequence of DNA bases, cytosine-adenine-guanine which is repeated multiple times (i.e. ... CAGCAGCAG ...) This is known as a trinucleotide repeat or CAG repeat. In patients with a mutated Htt gene there are more CAG repeats than normal which leads to the effects previously mentioned.
Normally people have <28 repeats but any number of repeats up to 35 will mean a person is NOT affected by Huntington's disease. 36-40 repeats result in a reduced-penetrance form of the disease. >40 repeats results in full penetrance form of the disease. The number of repeats is also correlated to the onset of the disease with a greater number of repeats often leading to an earlier onset.
As Huntington's is inherited down generations the number of repeats tends to increase and the severity of the disease gets worse.