The HTT Gene

The HTT gene, located on Chromosome 4, provides instructions for producing a vital protein called huntingtin. While the precise role of this protein remains unclear, it holds significance in nerve cells (neurons) within the brain and is crucial for normal development before birth. Although other functions of this protein post-birth are uncharacterised, it has been understood that it plays a crucial role in brain signalling and its activity is more pronounced in the brain. Inside cells, this protein is thought to partake in chemical signalling, transporting materials, cellular repair and safeguarding cells from self-destruction (apoptosis).  A specific segment within the HTT gene contains a DNA sequence known as a CAG trinucleotide repeat (Figure 1) . This segment comprises a series of three DNA building blocks (cytosine, adenine, and guanine) that repeat multiple times consecutively. Typically, the CAG segment repeats between 10 to 35 times within the gene. The huntingtin protein is broadly active and is essential for normal development, excessive production of this protein is linked to Huntington’s disease.

In its mutated form the HTT gene might acquire additional CAG trinucleotide repeats, resulting in the production of abnormal protein (Figure 2). This increase in the CAG repeats does not inhibit the protein production but result in protein accumulation. This accumulated protein over a period causes symptoms that are associated with Huntington’s disease.