CAG diseases are a group of hereditary neurodegenerative disorders characterized by the expansion of a CAG (cytosine-adenine-guanine) trinucleotide repeat within specific genes. This expansion leads to an abnormally long stretch of glutamine amino acids (a polyglutamine tract) in the resulting protein, causing the protein to misfold and aggregate, ultimately leading to neuronal dysfunction and cell death.
Understanding CAG Repeats and Polyglutamine Tracts
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CAG Repeats: These are repetitive sequences of the DNA building blocks cytosine (C), adenine (A), and guanine (G). Everyone has CAG repeats in their DNA, but individuals with CAG diseases have an abnormally high number of these repeats in specific genes.
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Polyglutamine (PolyQ) Tracts: The CAG repeat sequence in DNA is transcribed into mRNA, which is then translated into a protein. Each CAG triplet codes for the amino acid glutamine. Thus, an expanded CAG repeat region in a gene results in a protein with an abnormally long stretch of glutamine residues (a polyglutamine tract).
The Pathogenic Mechanism
The expanded polyglutamine tract causes the protein to:
- Misfold: The protein loses its normal three-dimensional structure.
- Aggregate: Misfolded proteins clump together, forming aggregates within neurons.
- Disrupt Cellular Function: These aggregates interfere with normal cellular processes, leading to neuronal dysfunction and death.
Examples of CAG Diseases
Several distinct neurodegenerative disorders are caused by CAG repeat expansions. Each disease is linked to a specific gene containing the expanded repeat. Here are some examples:
- Huntington's Disease (HD): Caused by a CAG expansion in the HTT gene (encoding Huntingtin protein).
- Spinocerebellar Ataxias (SCAs): A group of ataxias caused by CAG expansions in various genes, including:
- SCA1: ATXN1 gene
- SCA2: ATXN2 gene
- SCA3 (Machado-Joseph Disease): ATXN3 gene
- SCA6: CACNA1A gene
- SCA7: ATXN7 gene
- Spinal and Bulbar Muscular Atrophy (SBMA) or Kennedy's Disease: Caused by a CAG expansion in the AR gene (encoding the androgen receptor).
- Dentatorubral-pallidoluysian Atrophy (DRPLA): Caused by a CAG expansion in the ATN1 gene.
Symptoms and Diagnosis
Symptoms of CAG diseases vary depending on the specific disease and the affected brain regions. Common symptoms include:
- Movement disorders (ataxia, chorea)
- Cognitive decline
- Psychiatric problems
- Muscle weakness
Diagnosis typically involves:
- Clinical evaluation
- Family history assessment
- Genetic testing: To detect the presence and size of the CAG repeat expansion in the relevant gene.
Treatment and Management
Currently, there are no cures for CAG diseases. Treatment focuses on managing symptoms and improving quality of life. This may include:
- Medications to control movement disorders
- Physical therapy
- Occupational therapy
- Speech therapy
- Supportive care
Research is ongoing to develop disease-modifying therapies that can slow or halt the progression of these disorders.
In summary, CAG diseases are a class of genetic disorders resulting from expanded CAG repeats within specific genes, leading to the production of toxic polyglutamine-containing proteins that damage nerve cells and cause a variety of neurological symptoms.
