10 Questions
What is the consequence of having 36 or more glutamines in a row in the huntingtin protein?
Abnormal protein aggregation in neuronal cells
What is the primary mechanism by which the expanded CAG repeats affect the huntingtin protein?
Instability of the HTT gene during DNA replication
What is the likelihood that a child will inherit the affected gene if one parent has Huntington disease?
50%
What is the region of the brain most affected by the abnormal protein in Huntington disease?
Caudate and putamen of the basal ganglia
What is the term used to describe the type of disease caused by the expanded CAG repeats in Huntington disease?
Polyglutamine disease
What is the primary mechanism by which Huntington disease symptoms appear earlier in each generation?
Higher number of CAG repeats in the protein
What is the term for the alleles with 27-35 CAG repeats that don't cause the disease but can expand to become full mutations?
Pre-mutation alleles
Why do new disease alleles and anticipation generally occur when the father is the affected parent?
Because repeat expansion occurs more in the production of sperm than eggs
What is the minimum number of CAG repeats required for a person to show 100% penetrance and develop Huntington disease?
40 CAG repeats
Why is the test for HD, which counts the number of CAG repeats, generally good at determining whether HD will develop in an at-risk individual?
Because it can detect the number of CAG repeats, which correlates with penetrance
Study Notes
Huntington Disease (HD)
- A rare neurodegenerative disease caused by a repeated sequence of DNA that leads to an abnormal protein formation, resulting in abnormal movements and cognitive problems.
- An autosomal dominant genetic disorder, meaning one affected copy of a gene is enough to cause disease.
Genetic Characteristics
- Typically, the gene called huntingtin or HTT on chromosome 4 contains a triplet repeat of C, A, and G nucleotides 10-35 times in a row.
- In people with HD, this repeat goes on for 36 or more times in a row.
- The CAG repeat codes for the amino acid glutamine, resulting in 36 or more glutamines in a row in the huntingtin protein.
Effects of HD
- The mutated protein aggregates within the neuronal cells of the caudate and putamen of the basal ganglia, causing neuronal cell death.
- Cell death might be related to excitotoxicity, which is excessive signaling of these neurons, leading to high intracellular calcium.
DNA Replication and Repeat Expansion
- The expanded CAG repeats affect DNA replication, causing DNA polymerase to lose track of which CAG it's on, resulting in extra CAGs being added.
- This expansion occurs during cell divisions, leading to ample opportunities for repeat expansion, making the gene more unstable.
Anticipation and Inheritance
- The phenomenon of anticipation means that HD families often show earlier symptom onset with each generation.
- Children of a parent with HD can inherit even more CAG repeats than the parent, leading to an earlier age of symptom onset.
- Repeat expansion occurs more in the production of sperm than eggs, resulting in anticipation and new disease alleles when the father is the affected parent.
Penetrance and Diagnosis
- A person with 40+ repeats shows 100% penetrance and will have the disease.
- People with 36-39 repeats can show reduced penetrance, with some having symptoms while others may not.
- The test for HD, which counts the number of CAG repeats, is effective in determining whether HD will develop in an at-risk individual.
Test your knowledge of Huntington disease, a rare neurodegenerative disorder caused by an autosomal dominant genetic mutation leading to abnormal movements and cognitive problems.
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