Genetic medicine in systems

Question 1

how do pathogenic variants cause disease? (4 different ways)

Answer 1

1. null variants
2. gain of function variants
3. dominant negative variants
4. loss of heterozygosity

Question 2

what are null variants?

Answer 2

= when gene stops making peptide

• premature stop codon
• frameshift
• splice mutation
• gene deletion

e.g. marfan syndrome

Question 3

what is haploinsufficiency?

Answer 3

haploinsufficiency = less functioning protein so cell can’t make stuff it needs

Question 4

what is gain of function variants type of pathogenic variant causing disease?

Answer 4

= variant leads to peptide with gain of or new function

• missense variants
• activates the genes

e.g. hypochondroplasia

Question 5

what is dominant negative variants?

Answer 5

= variant leads to peptide that interferes with another peptide

• missense variant
• makes abnormal collagen

e.g. osteogenesis imperfecta type 2

abnormal collagen messes up normal peptide

2 peptides need to work together - 1 peptide messes with the other. variant leads to peptide that interferes with another peptide

Question 6

what is loss of heterozygosity?

Answer 6

= first null copy is inherited somatic loss of second copy

• fist null copy

inherits 1 germline variant - gets 2nd somatic variant means can no longer

second allele lost in cell

(i think it’s like the cancer - need 2 hits)

Question 7

when can genetic therapy be used? at what point?

Answer 7

at every point in central dogma

Question 8

how does treatment work for genetic diseases?

Answer 8

it has to be very highly specific - not just to disease but specific to the genetic variant

Question 9

how do you treat null pathogenic variants?

Answer 9

You need to replace the gene of the mRNA (as peptide has stopped being made due to premature stop)

Question 10

how do you treat gain of function or dominant negative mechanisms?

Answer 10

You need to reduce mutant gene expression

Question 11

what are the risks of integrating gene therapy?

Answer 11

• Disruption of important genes (“Off Target effects”)

Question 12

what is the negative of mRNA knockdown or mRNA gene replacement?

Answer 12

Need for repeated treatment

Question 13

what are the risks for viral vectors to deliver gene therapy?

Answer 13

• Immune reaction to the vector
• Immune reaction to the transfected cell

Question 14

what is the big negative for all the developments for genetic disease treatment?

Answer 14

unaffordable and unsustainable

Question 15

what are precision therapies targeted at?

Answer 15

specific causative variant (not everyone with a disease)