Understanding Huntington's Disease: Genetic Mutations and the Huntingtin Protein

Introduction

Huntington's Disease (HD) is a neurodegenerative disorder with a profound impact on both physical and mental health. Understanding the underlying genetic cause of this disease is critical for advancing research and potential therapies. This article delves into the specific genetic mutation responsible for Huntington's Disease and elucidates how it alters the huntingtin protein, leading to the symptoms and progression of the disease.

Details

• Genetic Mutation

  • The mutation responsible for Huntington's Disease occurs in the HTT gene located on chromosome 4.
    • The HTT gene encodes the huntingtin protein, which is crucial for neuronal function.
    • The mutation is characterized by an expanded CAG (cytosine-adenine-guanine) repeat sequence in the gene.
      • Normal individuals typically have 10 to 35 repeats.
      • In individuals with Huntington's Disease, the number of repeats is often 36 or more, with some having over 100 repeats.

• Effects on the Huntingtin Protein

  • The expansion of the CAG repeats leads to the production of an abnormally long huntingtin protein.
    • The normal huntingtin protein is involved in cellular processes such as vesicle transport, gene regulation, and apoptosis (programmed cell death).
    • The mutated huntingtin protein can misfold and aggregate, forming toxic inclusions within neurons.
      • These aggregates disrupt cellular functions and can trigger neurodegenerative pathways.
      • Accumulation of mutant huntingtin impairs mitochondrial function and increases oxidative stress.

• Pathophysiological Consequences

  • The alterations caused by the mutant huntingtin protein primarily affect the basal ganglia, a region of the brain responsible for motor control and cognitive functions.
    • This degeneration leads to characteristic symptoms of HD, including chorea (involuntary movements), dystonia (muscle contractions), and cognitive decline.
    • The onset of symptoms typically occurs in mid-adulthood, but juvenile forms can also arise due to extreme expansions in CAG repeats.

• Transmission and Inheritance

  • Huntington's Disease follows an autosomal dominant inheritance pattern, meaning:
    • An affected individual has a 50% chance of passing the mutated gene to offspring.
    • The severity of symptoms and the age of onset can vary widely, even among family members with the same mutation.

Conclusion

The genetic mutation responsible for Huntington's Disease is the expansion of CAG repeats in the HTT gene, leading to the production of a mutant huntingtin protein that disrupts cellular function and contributes to neuronal degeneration. Understanding this mutation and its effects is crucial for developing targeted therapies and providing support for affected individuals and families. Continued research into the molecular mechanisms of Huntington's Disease holds promise for future advancements in treatment and potential cures.