Huntington Disease Genetics - Bemis Flashcards
What is the name of the term in genetics that means a disease mutation can expand and get bigger consequently affecting younger/future generations at an earlier age? Relation to HD?
GENETIC ANTICIPATION
A parent with incomplete penetrance (36-40 poly Q repeats) may pass on a copy with an increased number of repeats resulting in a child with fully penetrant Huntington Disease.
What is the specific mutation associated with Huntington Disease?
- Large polyglutamine repeats in the “Huntingtin” protein (Htt)
- normal = 8-35
- HD = 40-121
What is the genetic inheritance pattern of HD?
- Autosomal dominant inheritance of mutation in Htt
- Chromosome 4p16.3
- expansion of a polymorphic CAG trinucleotide repeat
- 100% penetrance
Why are children with an HD positive father more likely to get HD?
Instability is greater in spermatogenesis, it is more likely in paternally inherited HD
What happens to the patient if they have 35 or less poly Q repeats?
Normal, no mutation, no disease, no risk to offspring
What happens to a patient if they have 36-41 polyQ repeats?
- Mutation = Incomplete penetrance
- May or may not have disease
- 50% risk to offspring
What happens if a patient has 40-60 polyQ repeats?
- Have mutation = full penetrance
- Adult onset HD
- 50% risk to offspring
What happens if a patient has 60+ polyQ repeats?
- Have mutation = full penetrance
- Juvenile onset of HD in some cases
- 50% risk to offspring
How is the NMDA receptor altered in HD?
Loss of NMDA receptor binding sites in Putamen
-variants in the NMDA receptor may influence disease severity
-modifier gene
How do poly Q repeats affect the Huntingtin protein?
- Makes protein insoluble
- Triggers the formation of protein aggregates
- traps things in aggregates (nucleic acid, protein, etc.)
- variable symptoms due to what gets trapped
- The polyglutamine repeat may be cleaved from the protein
- may function to cause cell death in neurons
