Huntingtin (HTT) Gene Mutation | How Does One Gene Dictate a Neurodegenerative Fate?

The huntingtin gene (HTT) provides the instructions for making a protein called huntingtin. While its full function is still under intense research, the normal huntingtin protein is crucial for the development and survival of neurons, the primary cells of the brain and nervous system. It plays significant roles in various cellular activities. For instance, it is involved in intracellular transport, which is the movement of essential molecules and organelles like mitochondria within the neuron. Think of it as a facilitator for the cell's internal logistics and delivery system. It also participates in cell signaling, helping neurons communicate with each other, and protects the cell from self-destruction, a process known as apoptosis. The protein is active throughout the body but is particularly important in the brain, which explains why a mutation in this single gene has such devastating neurological consequences. Its presence from before birth indicates its fundamental role in nervous system development. Without a functional huntingtin protein, neurons cannot maintain their complex structure or carry out their high-energy tasks efficiently, setting the stage for cellular stress and eventual breakdown.

The mutation responsible for Huntington's disease is a specific type of genetic error known as a trinucleotide repeat expansion. Within the HTT gene, there is a DNA segment where the three building blocks—cytosine, adenine, and guanine (CAG)—are repeated in sequence. In most individuals, this CAG segment repeats 10 to 35 times. However, in individuals who will develop Huntington's disease, this segment repeats 36 times or more. This expansion is the core defect. When the cell reads this "stuttering" genetic code, it produces an abnormally long and misshapen huntingtin protein. This mutant huntingtin protein (mHTT) is toxic to cells. It gets cut into smaller, more toxic fragments, which then misfold and clump together, forming aggregates inside neurons. These aggregates disrupt virtually every major cellular process, from energy production to waste disposal, ultimately leading to the death of the neuron. The length of the CAG repeat is directly correlated with the severity and age of onset of the disease; a higher number of repeats generally leads to an earlier onset.

The mutant huntingtin protein (mHTT) inflicts damage on neurons through a multi-pronged attack. Its primary mode of toxicity involves misfolding and aggregation. These protein clumps physically obstruct cellular machinery and sequester other essential proteins, preventing them from performing their functions. This process is particularly detrimental in specific brain regions, most notably the striatum and cerebral cortex, which are involved in controlling movement, mood, and cognition. The mHTT aggregates interfere with transcription (the reading of genetic information), disrupt the function of mitochondria (the cell's powerhouses), and impair axonal transport, which is critical for moving materials along the long neuronal projections. This cascade of dysfunction triggers chronic cellular stress and inflammation, culminating in programmed cell death (apoptosis). The selective vulnerability of certain neurons to this process explains the specific pattern of symptoms seen in Huntington's disease.

The delayed onset of Huntington's disease symptoms, typically appearing between the ages of 30 and 50, is a result of its progressive nature. Although the genetic mutation is present from birth, the neuronal damage is cumulative and takes years to reach a threshold where clinical symptoms become apparent. The brain has a remarkable capacity for compensation, and for a long time, the remaining healthy neurons can mask the dysfunction of the dying ones. However, as more and more cells in critical areas like the basal ganglia are lost, this compensatory mechanism fails. The rate of this neurodegeneration is influenced by the length of the CAG repeat; a larger number of repeats accelerates the toxic processes, leading to an earlier age of onset. This phenomenon is known as "anticipation," where the disease may appear at an earlier age in successive generations if the repeat length increases during transmission.

Huntington's disease is inherited in an autosomal dominant pattern. "Autosomal" means the mutated HTT gene is located on one of the non-sex chromosomes (autosomes), so it affects both males and females equally. "Dominant" means that only one copy of the mutated gene, inherited from just one parent, is sufficient to cause the disease. This gives the condition a predictable inheritance risk. If a parent has Huntington's disease, each of their biological children has a 50% chance of inheriting the mutated gene and, consequently, a 50% chance of developing the disease. Conversely, there is also a 50% chance of inheriting the normal copy of the gene from the affected parent, in which case the child will not develop the disease and cannot pass it on to their own children. This clear, strong pattern of inheritance makes it possible to trace the disease through family generations and is the basis for genetic counseling and predictive testing for at-risk individuals.