Lecture 31 Flashcards
What are multifactorial disorders?
1) Predominantly autosomal dominant
2) Mutations of many genes are involved
3) Mutations predispose, but don’t guarantee disease (variable penetrance)
4) Contributions of environmental influences are significant, but gene vs. environment contributions are highly variable
What is thrombophilia?
Thrombophilia is the propensity to form blood clots within blood vessels: Deep Vein Thrombosis (DVT)
What is the primary cause of pulmonary embolism?
Deep Vein Thrombosis (DVT)
How many people are hospitalized and die respectively per year in the US due to Pulmonary embolisms (PE)?
500,000; 100,000
Half of all Deep Venous Thrombosis (DVTs) are due to _________
Genetic predisposition
A problem/mutation in the clotting factor cascade will result in ______
Hemophilia
How does the body prevent thrombin from activating fibrinogen and forming blood clots?
Thrombin is converted to a thrombomodulin-thrombin complex
What is the function of the thrombomodulin-thrombin complex?
The thrombomodulin-thrombin complex cleaves protein C for its activation
What is the function of activated protein C?
Activated protein C finds any factor 5 and factor 8 and degrades them to their inactive forms
What is the disease Factor 5 Leiden caused by?
G to A mutation (G1691A) causes Arg (Arginine) for Gln (Glutamine) substitution in protein
What happens in individuals with Factor 5 Leiden?
1) They retain their coagulation activity, however the blood clotting pathway cannot be inactivated by protein C
2) The result is increased blood clotting
What is a mutation that can occur in prothrombin?
1) G to A mutation (G20210A) in 3’ UTR results in overly stable mRNA
2) Results in increase blood clotting
What is a similarity between a mutation in Prothrombin and a mutation in Factor 5 Leiden?
Both mutations result in an overabundance of coagulation proteins within vessels and accounts for the vast majority of the genetic predisposition to thrombophilia
What are examples of common neutral polymorphisms?
1) SNPs
2) VNTRs
What are examples of functional polymorphisms?
1) SNPs in genes (factor 2 or 5)
2) CNVs
What are examples of rare mutations?
1) Missense (CF)
2) Microdeletion (PWS)
Where do functional polymorphisms derive from?
Inherited from parents. They are usually not de novo mutations
Functional polymorphisms result in:
1) Predisposition to disease: source of non-penetrance
2) Common DNA variant in the population
What are environmental risks for thrombophilia?
1) Prolonged immobility - long plane flights, trauma or surgical recovery
2) Pregnancy
3) Birth control pills & hormone replacement therapy
What are ways to avoid or deal with thrombophilia?
1) Genetic testing for two mutations (Factor 5 Leiden + Prothrombin) - If there is a family history
2) Avoidance of environmental factors - extended immobility & birth control estrogen
3) Anti coagulant therapy (aspirin, heparin, & coumadin) tailored to degree of risk
What are two developmental disorders that cause heart defects?
1) Holt-Oram syndrome (congenital disorder)
2) Atrial-septal defect (congenital disorder)
What is Holt-Oram syndrome caused by?
A loss in the TBX5 transcription factor
What is Atrial-septal defect caused by?
A loss in the NKX2-5 transcription factor
What are two types of cardiomyopathies that cause heart defects?
1) Hypertrophic cardiomyopathy
2) Dilated cardiomyopathy
What can hypertrophic cardiomyopathy be caused by?
Loss of muscle contraction (force generation) function due to mutations in:
1) Beta myosin heavy chain
2) Myosin essential light chain
3) Myosin regulatory light chain
4) Troponin T
5) Troponin I
6) Cardiac myosin binding protein C
7) A tropomyosin
What can dilated cardiomyopathy be caused by?
Loss of muscle contraction (force transduction) function due to mutations in:
1) Dystrophin
2) Actin
What are two types of arrhythmias that cause heart defects?
1) Long QT syndrome
2) Brugada syndrome
What can Long QT syndrome be caused by?
Potassium channel defects due to mutations in:
1) KVLQT1
2) Herg
3) Mink
Sodium channel defects due to a mutation in:
1) SCN5A
What can Brugada syndrome be caused by?
Sodium channel defects due to a mutation in:
1) SCN5A
What is Long QT syndrome?
Mutations in potassium channels cause slow repolarization of membrane causing long QT interval
What does Long QT syndrome result in?
1) Predisposition to Arrythmia
2) Sudden death
What are treatments for Long QT syndrome?
1) Pacemaker
2) Drug therapies
What is common among all MYBPC3 mutations that cause hypertrophic cardiomyopathy?
1) They are all knockout mutations (splice site mutations, deletions, missense mutations, frameshift mutations)
2) They are not fatal events. They only predispose you to hypertrophic cardiomyopathy
What is common among all MYH7 mutations that cause hypertrophic cardiomyopathy?
1) They are all functional SNPs (nothing that gives you a knockout)
2) They are not fatal events. They only predispose you to hypertrophic cardiomyopathy
How is Hypertrophic Cardiomyopathy treated?
1) Genotyping array can be done to identify defective gene and confirm clinical diagnosis
2) Treat patient with appropriate targeted drug or gene therapy
3) All patients get an implanted defribrillator
4) Test normal family members to identify people at risk before clinical symptoms appear
What is the most common cause of sudden death in young adults?
Hypertrophic cardiomyopathy
How common is hypertrophic cardiomyopathy?
1/400; it is a common, mostly familial disorder
What is Alzheimer disease?
It is a CNS neurodegenerative disorder that is associated with progressive loss of cognitive function and dementia
What can Alzheimer disease result in?
Death from malnutrition (forget to eat), infection and heart disease (can be from bad diet)
What is Alzheimer disease caused by?
Defects of beta-amyloid precursor protein (APP) metabolism is proximate cause of Alzheimer disease (AD): there is an accumulation of beta-amyloid peptide (A-beta40 or 42)
What are two forms of Alzheimer Disease (AD) and what their respective percentage contributions to AD?
1) Early onset autosomal dominant AD (5%)
2) Late onset classic AD (95%)
What is early onset autosomal dominant AD caused by?
Mutations in three genes:
1) APP (amyloid precursor protein)
2) Presenilin1
3) Presenilin2
What is late onset classic AD caused by?
Three common polymorphic variants of apolipoprotein E that differ by one amino acid (we each have two of these alleles):
1) E2 (10%; protective)
2) E3 (65%; neutral)
3) E4 (25%; risk for AD)
What are two intimately related diseases relating to fat and sugar?
Obesity and Type II diabetes (dysregulation of fat and sugar metabolism, respectively) - complex highly regulated biochemical pathways with many, many low penetrance genes involved
How does the process of excess fat detection and response work?
1) When adipocytes (fatostat) sense that the fat stores in the adipocytes are too high, they start to produce Leptin
2) Leptin crosses the blood brain barrier and impinges on the hypothalamus (OBRb gene)
3) Signals go out to tissues in the body causing downstream events: effects of leptin on tissues - expend energy stores (sugars and fats) and ingest less (sugars and fats)
a) Adipose
i) Increase triglyceride oxidation
ii) Increase uncoupling protein (UPC) synthesis
iii) Decrease fatty acid synthesis
b) Skeletal muscle
i) Increase glucose and fatty acid uptake
ii) Increase glucose and fatty acid oxidation
c) Hypothalamus
i) Increase physical activity and energy expenditure
ii) Decrease appetite
4) Leptin secretion by adipocytes decreases as fat stores dwindle
How can genes, aging & obesity trigger diabetes?
1) Genes, Aging, & Obesity cause muscle insulin resistance
2) Increased lipolysis in visceral fat causes increased fatty acids
3) Beta Cell compensation causes hyperinsulinemia
4) Increased gluconeogenesis in the liver causes increased glucose output
5) Beta Cell Decompensation along with the above steps causes impaired glucose tolerance
6) Decreased insulin secretion (Type II Diabetes)
7) Diabetes
