The HTT gene, located on chromosome 4, contains the genetic instructions for creating the huntingtin protein. A mutation in this single gene causes Huntington’s Disease (HD), a fatal neurodegenerative disorder. HD leads to the progressive deterioration of nerve cells in the brain, profoundly affecting movement, cognition, and mental health. Understanding the gene and the resulting toxic protein provides the foundation for developing future treatments.
The Normal Functions of the Huntingtin Protein
The huntingtin protein (Htt) is expressed throughout the body, but it is particularly abundant in the brain and testes. It is a large protein, and its precise molecular role remains under investigation. Htt is necessary for cell survival and development. During embryonic development, Htt is required for processes like gastrulation and neurogenesis.
In the adult nervous system, normal Htt performs several protective and regulatory functions. It acts as an anti-apoptotic factor, preventing programmed cell death in neurons. Htt regulates the expression of various genes necessary for neuronal health, such as brain-derived neurotrophic factor (BDNF). The protein also facilitates axonal and vesicular transport, moving essential materials like mitochondria along nerve cell extensions. Normal Htt is crucial for the survival of striatal neurons, the cells most damaged in Huntington’s Disease.
The Mechanism of HTT Gene Expansion
The genetic error causing Huntington’s Disease is an unstable trinucleotide repeat within the HTT gene, consisting of a repeating sequence of Cytosine-Adenine-Guanine (CAG) bases. A healthy HTT gene typically contains between 10 and 26 CAG repeats.
The pathological mutation occurs when the number of CAG repeats expands to 40 or more. Individuals with 36 to 39 repeats have reduced penetrance alleles, meaning they may develop the disease later in life. This expanded CAG sequence is translated into a long stretch of glutamine amino acids, known as a polyglutamine (polyQ) tract, in the huntingtin protein.
The expanded polyQ tract causes the huntingtin protein to misfold and aggregate, leading to a toxic gain-of-function. The mutant protein (mHtt) interferes with normal cellular processes, including transcription, transport, and protein degradation. This toxicity is particularly damaging to the medium spiny neurons in the striatum, a brain region involved in motor control, leading to their dysfunction and death. The length of the expanded CAG repeat is inversely correlated with the age of disease onset; a greater number of repeats means an earlier onset.
Clinical Progression of Huntington’s Disease
Huntington’s Disease is a progressive condition that manifests through a combination of motor, cognitive, and psychiatric symptoms. Onset typically occurs in mid-life, between the ages of 30 and 50. Juvenile HD (JHD), occurring before age 20, is associated with very high CAG repeat numbers.
The most recognizable motor symptom is chorea, presenting as involuntary, jerky movements of the limbs, trunk, and face. As the disease advances, chorea may be replaced by dystonia (sustained muscle contractions) and bradykinesia (slowness of movement), leading to severe balance and gait issues. Difficulties with swallowing and slurred speech also develop in the middle and late stages.
Cognitive decline involves executive dysfunction, which impairs the ability to plan, organize, and think abstractly. Memory loss and difficulty learning new information also occur. Psychiatric symptoms often precede or accompany the motor and cognitive changes, including mood swings, irritability, depression, and obsessive-compulsive behaviors. The average duration from onset to death is about 15 to 20 years.
Inheritance and Diagnostic Testing
Huntington’s Disease follows an autosomal dominant inheritance pattern. A person only needs to inherit one copy of the expanded HTT gene from either parent to develop the disorder. Each child of an affected parent has a 50% chance of inheriting the mutated gene.
The disease is considered fully penetrant with 40 or more CAG repeats, meaning nearly everyone who inherits the expanded gene will eventually develop the condition. Genetic testing determines the number of CAG repeats and is used in two primary contexts: diagnostic and predictive.
Diagnostic Testing
Diagnostic testing is performed on individuals already exhibiting symptoms to confirm the clinical diagnosis.
Predictive Testing
Predictive testing is available for at-risk individuals who are currently healthy but wish to know their genetic status before symptoms appear. This choice carries significant ethical and psychological weight, as a positive result confirms an inevitable, currently incurable disease. Genetic counseling is an integral part of the process to ensure informed consent and to address potential emotional distress, family dynamics, and discrimination concerns.
Emerging Therapeutic Strategies
Current management focuses on palliative and symptomatic care, using medications to control motor symptoms like chorea and manage psychiatric issues. However, the most promising research efforts are centered on therapies that target the root cause of the disease—the toxic mutant huntingtin protein. These new approaches are referred to as huntingtin-lowering strategies.
One major strategy involves gene silencing, primarily through the use of antisense oligonucleotides (ASOs). ASOs are short, synthetic single-stranded DNA molecules administered into the cerebrospinal fluid via a lumbar puncture. Once delivered, the ASOs bind to the messenger RNA (mRNA) produced by the HTT gene, triggering the degradation of the mRNA and reducing the production of the huntingtin protein.
Researchers are developing both non-selective ASOs, which lower both the normal and mutant protein, and allele-selective ASOs, which aim to target only the toxic mutant protein while preserving the function of the normal protein. Other strategies include using adeno-associated virus (AAV) vectors to deliver RNA interference constructs for sustained gene silencing, and gene editing techniques like CRISPR-Cas9. These approaches represent a shift toward disease-modifying treatments that could potentially halt or significantly slow the progression of Huntington’s Disease.