Genetics of Huntington's disease: the expanding code of CAG repeats

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Genetics of Huntington's disease: the expanding code of CAG repeats
Genetics of Huntington's disease: the expanding code of CAG repeats

Huntington's disease (HD) is a devastating neurodegenerative disorder that has puzzled scientists and clinicians for decades. One of the key mysteries surrounding HD lies in its genetic origins. The disease is caused by a mutation in a specific gene, and its onset and progression are intricately tied to the expansion of CAG repeats. In this article, we will delve into the genetics of Huntington's disease, shedding light on the role of CAG repeats and their impact on the development and progression of this debilitating condition.

The HD Gene: HTT

Huntington's disease is primarily associated with a mutation in a single gene known as HTT, short for huntingtin. This gene is located on chromosome 4 and encodes a protein called huntingtin. In its normal form, huntingtin plays a crucial role in various cellular functions. However, a mutation in the HTT gene results in the production of a mutated form of the huntingtin protein, leading to the development of HD.

The CAG Repeat Expansion

The genetic mutation responsible for HD is characterized by an expansion of CAG repeats within the HTT gene. CAG is an abbreviation for cytosine-adenine-guanine, which are the three nucleotide bases that make up the DNA sequence. In individuals without HD, the number of CAG repeats typically ranges from 10 to 35.

However, in those affected by HD, there is an abnormal expansion of these CAG repeats. The most common threshold for the onset of symptoms is when the number of CAG repeats exceeds 40. The more CAG repeats present in the HTT gene, the earlier the onset of symptoms and the more severe the disease's manifestations.

Mechanism of CAG Repeat Expansion

The exact mechanism by which CAG repeats expand is still an area of active research. It is believed that the expansion occurs during DNA replication, a process in which the DNA molecule is copied to create new cells. In individuals with HD, the HTT gene tends to be unstable, leading to the addition of extra CAG repeats with each replication cycle.

Consequences of CAG Repeat Expansion

The expansion of CAG repeats has profound consequences for the HTT gene and the resulting huntingtin protein. The mutated huntingtin protein, containing an abnormally high number of CAG repeats, is prone to misfolding and aggregating in the brain. These aggregates, known as "polyglutamine aggregates," disrupt normal cellular processes, cause neuronal damage, and ultimately lead to the symptoms and neurodegeneration characteristic of HD.

Genetic Testing and Predictive Testing

The knowledge of the CAG repeat expansion in HD has enabled genetic testing for the disease. Individuals with a family history of HD may undergo genetic testing to determine their CAG repeat count. This predictive testing can provide information about the likelihood of developing HD later in life. However, it is a complex decision, as it has profound psychological and emotional implications.

The genetics of Huntington's disease are intrinsically tied to the expansion of CAG repeats within the HTT gene. The greater the number of CAG repeats, the earlier the onset and more severe the progression of the disease. Understanding this genetic basis is crucial not only for diagnosing and managing HD but also for ongoing research into potential treatments and therapies aimed at modifying or halting the expansion of CAG repeats. The genetics of Huntington's disease represent both a complex puzzle and a beacon of hope for future interventions in the fight against this devastating disorder.

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