Cag trinucleotide repeat expansion

Definition

CAG trinucleotide repeat expansion refers to a genetic phenomenon where the DNA sequence 'CAG' is repeated multiple times within a gene, leading to abnormal protein function and various neurodegenerative disorders. This expansion is particularly notable in disorders such as Huntington's disease, where the excessive repetition results in a toxic gain of function in the huntingtin protein, contributing to neuronal degeneration and movement disorders.

5 Must Know Facts For Your Next Test

1. CAG repeats can vary in length among individuals, with more than 35 repeats commonly associated with the onset of Huntington's disease.
2. As CAG repeat length increases, the age of onset and severity of symptoms tends to worsen, highlighting a clear relationship between repeat number and disease progression.
3. The CAG expansion leads to an abnormal huntingtin protein that aggregates in neurons, disrupting normal cellular processes and leading to cell death.
4. Other conditions related to CAG expansions include spinocerebellar ataxias and certain forms of muscular dystrophy, illustrating the broader impact of this genetic alteration.
5. Research into therapies for diseases caused by CAG repeat expansions includes gene editing approaches aimed at reducing or correcting the faulty repeats.

Review Questions

• How does the CAG trinucleotide repeat expansion contribute to the pathophysiology of Huntington's disease?
  • The CAG trinucleotide repeat expansion in the HTT gene leads to an elongated polyglutamine chain in the huntingtin protein. This abnormal protein aggregation is toxic to neurons, causing their degeneration and leading to the hallmark symptoms of Huntington's disease such as involuntary movements and cognitive decline. The relationship between the length of the CAG repeat and the severity of symptoms further illustrates its critical role in the disease mechanism.
• Compare the effects of CAG repeat expansions in Huntington's disease and other polyglutamine disorders.
  • CAG repeat expansions cause similar pathophysiological effects across various polyglutamine disorders by producing proteins with elongated glutamine sequences that aggregate within neurons. In Huntington's disease, this leads specifically to movement disorders and cognitive decline. However, other polyglutamine disorders may manifest differently; for example, spinocerebellar ataxias primarily affect balance and coordination. Despite these differences, all share a common mechanism involving protein misfolding and neurodegeneration due to CAG expansions.
• Evaluate potential therapeutic strategies targeting CAG repeat expansions and their impact on neurodegenerative diseases.
  • Therapeutic strategies focusing on CAG repeat expansions include gene editing technologies like CRISPR-Cas9 aimed at directly modifying or reducing the number of CAG repeats in affected genes. These approaches have shown promise in preclinical models by alleviating some of the toxic effects associated with expanded repeats. Additionally, therapies that promote cellular clearance mechanisms for misfolded proteins are being explored. If successful, these strategies could significantly alter the course of neurodegenerative diseases linked to CAG expansions by addressing their underlying genetic causes.

Related terms

Huntington's Disease: A genetic disorder caused by the CAG repeat expansion in the HTT gene, characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms.

Polyglutamine Disorders: A group of neurodegenerative diseases, including Huntington's disease, where CAG repeat expansions lead to the production of proteins with elongated glutamine residues, causing cellular toxicity.

Neurodegeneration: The progressive loss of structure or function of neurons, which can be a consequence of various genetic mutations, including those caused by CAG repeat expansions.