What Happens When the HTT Gene is Mutated?

The HTT gene, responsible for encoding the Huntingtin protein, resides on the 4th chromosome among the 23 pairs. This protein exists in every cell, and when the gene mutates, it produces excessive protein leading to its accumulation. The HTT gene comprises a sequence of three building blocks—CAG-CAG-CAG. Individuals with 26 or fewer CAG repeats typically don’t face the risk of developing Huntington’s disease. However, those with more than 26 repeats might have implications for themselves or their children.

When the CAG repeats range from 27 to 35, it’s termed an ‘instable CAG tract,’ which becomes significant when planning a pregnancy due to a phenomenon known as ‘Anticipation.’ This phenomenon elevates the risk for subsequent generations, although individuals with these repeats might not develop symptoms themselves. Exceeding 36 repeats is considered ‘pathogenic,’ heightening the risk of developing Huntington’s disease during one’s lifetime. However, this doesn’t guarantee symptom onset, as there are further classifications.

CAG repeat length	Classification	Disease causing?	Consequences for offspring?
Below 26	Normal	No	Equivalent to the general population risk.
27 – 35	Intermediate	No	Instable CAG tract might result in having children with disease causing number of repeats.
36 – 40+	Pathogenic	36-39: May be not	50% risk with every pregnancy.
36 – 40+	Pathogenic	40 or more: Yes, with increasing age	50% risk with every pregnancy.

Individuals with 36-39 repeats, if tested before symptom onset, might never exhibit symptoms due to factors like age or other modifying genes. This variability is known as ‘reduced penetrance,’ where some individuals never manifest symptoms throughout their lives. Conversely, those with more than 40 repeats tend to develop Huntington’s disease symptoms, which worsen with age. New insights into gene interactions, the impact of our environment on genes, and the progress in genomics have uncovered additional factors influencing disease progression in those with a positive gene test.

With an understanding of what causes someone to develop symptoms of Huntington’s disease, click below to understand how mutated genes can be passed through multiple generations.