The HTT Gene: Function, Mutation, and Huntington’s Disease

The HTT gene, or huntingtin gene, holds the instructions for creating a protein called huntingtin. This protein is produced in cells throughout the body but is most active within the brain. The huntingtin protein is necessary for the normal development of an embryo before birth and is particularly active in nerve cells, known as neurons.

Normal Function of the Huntingtin Protein

The huntingtin protein is a versatile component within the nervous system, especially in the brain. One of its primary roles is to support the production and transport of brain-derived neurotrophic factor (BDNF). BDNF is a substance required for the survival and activity of neurons in specific brain regions, and huntingtin helps ensure it gets where it needs to go.

Huntingtin helps manage the movement of vesicles, which are small sacs that transport materials along a neuron’s long axons. This transport system is fundamental for chemical signaling between neurons and for delivering components throughout the cell. The protein is also involved in anchoring parts of the cell’s internal scaffolding, providing structural stability.

The huntingtin protein also has anti-apoptotic properties, meaning it helps protect the neuron from programmed self-destruction, a process that can be triggered by stress or damage. By interacting with other proteins in this pathway, huntingtin helps maintain the health and longevity of neurons.

The CAG Repeat Mutation

Within the HTT gene lies a repeating sequence of three DNA building blocks: cytosine, adenine, and guanine, known as a CAG trinucleotide repeat. In most of the population, this CAG segment is repeated a stable number of times, under 27. This normal variation allows for the production of a functional huntingtin protein, but a mutation occurs when this segment expands and becomes unstable.

This expansion is categorized into different ranges. An individual with 27 to 35 repeats has an “intermediate” allele; they will not develop the disease but may be at risk of passing an expanded gene to their children. A count of 36 to 39 repeats falls into a “reduced penetrance” category, where an individual may or may not develop symptoms. A count of 40 or more CAG repeats is “full penetrance,” meaning individuals with this number will almost certainly develop the disease.

The instability of the CAG repeat can lead to genetic anticipation. As the mutated gene is passed from one generation to the next, the number of CAG repeats can increase, which is particularly common when the gene is inherited from the father. A larger number of repeats is associated with an earlier age of symptom onset and a more severe disease course.

Consequences of the Mutation

The expansion of the CAG repeat segment in the HTT gene alters the instructions for building the huntingtin protein. This genetic error leads to the creation of an abnormally long version of the protein, which contains an extended tract of an amino acid called glutamine. This elongated protein, often called mutant huntingtin (mHTT), is unable to fold into its correct shape and perform its normal duties.

Instead of supporting the cell, the misfolded mHTT protein becomes toxic. It is cut into smaller, harmful fragments that stick to one another and to other cellular components. These fragments clump together inside neurons, forming dense aggregates in the cell’s nucleus and cytoplasm. The presence of these aggregates disrupts cellular processes, from gene transcription and energy production to the transport of materials.

This cellular disruption leads to the death of the neuron. The process is particularly damaging in brain regions that control movement, thought, and emotion, such as the striatum and the cerebral cortex. The progressive loss of these nerve cells is the underlying cause of Huntington’s disease, a neurodegenerative disorder characterized by worsening motor, cognitive, and psychiatric symptoms.

Inheritance and Genetic Testing

The mutated HTT gene is passed down through families in an autosomal dominant inheritance pattern. This means that inheriting just one copy of the mutated gene from a single parent is sufficient to cause the disease. A child of a parent who carries the mutation has a 50% chance of inheriting the gene and developing Huntington’s disease, and this risk applies to each child independently.

Genetic testing can identify the CAG repeat expansion in the HTT gene. For individuals with a family history of the disease who do not yet show symptoms, predictive testing can determine whether they carry the mutated gene. This is a personal decision that requires careful consideration and is accompanied by genetic counseling. For individuals already exhibiting symptoms, diagnostic testing can confirm a diagnosis of Huntington’s disease.

Options are available for prospective parents concerned about passing the gene to their children. Prenatal testing can determine the genetic status of a fetus during pregnancy. Another option is preimplantation genetic diagnosis (PGD), which is used with in vitro fertilization (IVF). This technology allows for the screening of embryos for the HTT gene mutation before implantation, enabling parents to select embryos that do not carry the expanded repeat.