Lecture 12: Repeat expansions and Huntington Disease

What are unstable repeat expansions?

• Definition: short DNA repeats (e.g., CAG, CGG) that abnormally expand.

• Inheritance: repeats increase across generations (slippage/unequal crossing over).

• Effect: disrupt gene expression or protein function.

What is slipped mispairing?

• During DNA replication: new strand slips and re-anneals out of alignment → repeat loop forms.

• Result: extra repeat added to daughter strand → repeat expansion over generations.

What are the 3 classes of unstable repeat expansions?

• Class 1: noncoding expansion → loss of protein function (Fragile X).

• Class 2: noncoding expansion → novel toxic RNA properties.

• Class 3: coding expansion → novel toxic protein properties (Huntington Disease).

What is Huntington Disease (HD)?

• Autosomal dominant neurodegenerative disorder; gene IT15/HTT on chromosome 4p16.3.

• Incidence: 3-7/100,000 in Western Europeans; much rarer in Japanese.

• Average age of onset: 40-45 years; death 15-20 years after onset.

• CAG repeat expansion in first exon of huntingtin gene (HTT).

What are the progressive phenotypes of HD?

• Onset: movement disorder (chorea), cognitive decline, behavioral/personality changes.

• Full spectrum: eye movement abnormalities, dysarthria (slurred speech), dysphagia (trouble swallowing), ataxia, myoclonus (sudden muscle jerks).

• Late stage: dystonia → rigid, akinetic (very little movement), demented, mute.

• Death from aspiration pneumonia due to immobility and dysphagia.

What are the CAG repeat ranges in HD?

• Normal: 9-35 repeats (average 18-19).

• Reduced penetrance: 36-39 repeats (may or may not develop HD).

• Fully penetrant: ≥40 repeats → HD certain.

• 40-55 repeats = adult onset (90% of HD carriers).

• 60-70 repeats = early/childhood onset (Juvenile HD).

  • Larger expansion = earlier onset.

• Repeat size explains ~72% of onset variation, not 100%

What is Juvenile HD (JHD)?

• Onset before age 20; caused by >60-80 CAG repeats.

• More rapid progression than adult-onset HD.

• Called the Westphal variant.

• Almost always due to paternal transmission (sperm have greater repeat expansion).

Why is HD transmitted paternally more severely?

• Sperm undergo far more cell divisions than eggs → greater instability.

• Repeat expansions (73%) are more common than contractions (23%) in sperm.

• Paternal transmission drives anticipation in HD.

What are the pathogenic cellular mechanisms of HD?

• Normal HTT = neuronal caretaker: transport, transcription, survival

• Mutant HTT (Huntingtin) protein folds incorrectly → broken into toxic pieces.

• Pieces go into the nucleus → clump together → disrupt gene activity.

• Pieces also clump in the cytoplasm → stress the cell’s cleanup system.

• Result: neurons don’t communicate well, mitochondria fail, energy drops, axons can’t transport materials properly.

What accounts for age of onset variation in HD?

• CAG repeat length accounts for ~72% of age of onset variation.

• Remaining ~28% is influenced by modifier genes and environment.

• 84% of residual variation is familial; heritability of onset ~40%.

• Family members with identical repeat lengths can still have different ages of onset.