From Gene to Function to Clinic (13) Flashcards
Mary-Claire King
- Identified BRCA
- Humans and chimpanzees 99% genetically identical
- Applying genomic sequencing to identify victims of human rights abuses
BRCA 1 and 2
Increases risk of breast cancer to 85% by 70, increases risk of developing ovarian cancer 2 > 55% (BRCA1) and 25% (BRCA2)
Advantages testing BRCA mutations
- Relief
- Better response if specific BRCA treatment
- Preventative measures - tamoxifen
- Other family members may get tested
Disadvantages testing BRCA mutations
- Worried
- Tell family members
- Test negative might think never get breast cancer
- Test positive - life/health insurance problems
Prophylactic surgery
- Remove ovaries reduces risk by 85%
- Preventative mastectomy reduces risk by 90%
Pre-symptomatic screening
Predict but can’t prevent, late onset disorders - Huntington’s, Retinitis pigments, Breast cancer, colon cancer
Treacher Collins syndrome
Crania-Facial demorphology syndrome - failure of neural crest cells to migrate and form structures of face
Symptoms of Treacher Collins syndrome
Small chin, narrowed constricted airways > tracheotomy, ‘man with sad eyes’
Pre-natal screening for Treacher Collins syndrome
Immediately put in breathing tube
Prenatal diagnosis
- Amniocentesis (17 weeks)
- Chorionic villus sampling (11 weeks)
- Maternal peripheral blood (sex)
- New non-invasive method based on NGS of mothers blood (10 weeks)
Preimplantation diagnosis
Non-disclosure testing (without disease status of parents, Huntingtons) or HLA typing to match cord blood stem cells for siblings
Problems associated with obesity
Coronary artery diseases, high blood pressure, type 2 diabetes, osteoarthritis, certain cancers
Percentage of people overweight
46% men, 32% women
Percentage of additional people obese
17% men, 21% women
Obesity and heritability
BMI 70-80% heritability
Leptin
Hormone released from fat cell leads to decrease in food intake, increase in thermogenesis, an increase in physical activity which all lead to decrease in fat cell mass, can have leptin replacement therapy
Gene therapy
Use of genetic material (DNA/RNA) as medicine
Leber’s congenital amaurosis (LCA)
Recessive, rare inherited eye disorder, blindness at birth/infancy, accounts for 10-18% of all congenital blindness, 18 genes implicated
Eye
Immune privileged and accessible for sub retinal injection
LCA mutation
In RPE65, photons hit retina > retinol > retinal pigmented epithelium, enzyme converts it back where it can receive photon again, enzyme is defective > poor vision
Problems with LCA therapy tests
Retina must be structurally norma, single gene loss of function, missense mutations only, amblyopia (lazy eye) may inhibit result)
Pharmacogenetics
Correlation between effect of drugs and genetic constitution of patients
What percentage of hospital admission are due to adverse drug response?
5-7%
Cytochrome P450 oxidases
Multilane family of enzymes found in liver
What are Cytochrome P450 oxidases involved in?
Metabolic elimination of most drugs and convert pro-drugs > active form e.g. codeine
CYP2D6
Highly polymorphic cytochrome 450 family member, metabolises 25% of drugs
What percentage of caucasians are non-metabolisers?
6-10%, no active CYP2D6
What percentage of caucasians are ultra-rapid metabolisers?
7%, multiple copies of CYP2D6
Tamoxifen metabolism
CYP2D6 rate limiting step converting tamoxifen > active metabolite/endoxifen
