Foundations 1 Test MIsc Week 1-2 Flashcards
Allelic heterogeneity
one disease caused by different mutations in the same gene
Locus Heterogeneity
one disease caused by different mutations in different (but related) genes
Clinical Heterogeneity
disease with different phenotypes that are caused by mutations in the same gene (when you have Type I, Type II… of disease)
what are the two largest contributors to genetic diversity between individuals?
SNPs (most common) and Copy number variants (second most common).
Role of CNVs? what are they?
variation in number of copies in one or more sections of DNA. important in development of special senses
Tandem repeats: types? role (general)?
Satellites, minisatellites, microsatellites. Generally found in non-coding regions of DNA and play a structural or protein binding role. Ex: telomeres (minisatellites) prevent chromosome shortening, alpha-satellites form binding site for kinetichore in all chromosomes
non-sense mutation
premature stop codon
missense mutation
code for new AA
silent mutation
code for same AA
proteins synthesized by free ribosomes are destined for (4)?
nucleus, mitochondria, peroxisome, cytosol
what is the role of signal peptides?
direct proteins where to go. Nucleus, mitochondria, ER
what the difference between free ribosomes and ER bound ribosomes
nothing other than their location. ER ribosomes are directed to the ER only after they translate a protein containing an ER localization protein
Contrasted to the signal peptides that locate a protein to the nucleus or mito, where does the signal peptide that localizes a protein to the ER end up?
in the ER membrane (where it is eventually degraded)
In what gene is the sickle cell mutation? What is the mutation
Beta globin. Glu6Val mutation
Compare the lifespan of a normal RBC to that of a sickle cell
Normal=120 days
Sickle=10-20 days
What is the role of MUTYH? What condition results from Biallelic LOF?
MUTYH is responsible for BER of 8-oxo guanine nucleotides. Without, MAP occurs (colon polyps)
What is the rationale behind using PARP1 inhibitors to treat breast cancer in individuals with BRCA1/2 mutations.
PARP1 is responsible for the repair of ssDNA. BRCA1/2 mutants have lost the ability to repair dsDNA. Eliminating these cells only remaining metho to repair DNA breaks (PARP1 inhibitors) will cause cell death.
What proteins should you associate with the repair of dsDNA breaks?
BLM, ATM, FANC, BRCA1/2, NBN
What is the diagnostic test for sickle cell anemia
Electrophoresis Hbs does not move as far on the gel
What is trisomy 18? Symptoms?
XY, 47, +18. Posteriorly rotated ears, small features with large head, unusual fingers (2nd and 5th digit overlap)
What is Patau syndrome??? Features?
Trisomy 13. Midline abnormalities (cleft lip, heart defects, brain and SC abnormalities)
What is a robertsonian translocation?
A translocation involving two Acrocentric chromosomes. Results in individuals that have a full amount of DNA but are lacking a chromosom, this is problematic for reproduction (if it is in the germ-line)
What occurs during pre-mRNA processing?
Introns are removed, 3’ poly A tail is added, 5’ cap is added
What is the inheritance of sickle cell?
Auto recessive
What is the general difference between thalassemia and sickle cell.
Sickle: abnormally shaped RBCs that are Lysed due to their shape
Thalassemia: a decreased amount of Hb subunits (alpha or beta) created causing a decreased (decreased number of hypochromic RBCs) amount of RBCs
What would be expect to see an increase in blood of in individuals with sickle cell?
Increased reticulocytes, increased products of hemolysis (Fe, bilirubin)
DMD vs. BMD
DMD is a more severe form of BMD in which Dystrophin is absent. Dystrophin is truncated in DMD. This causes muscle weakness in skeletal and cardiac muscle
DMD inheritance
X-linked recessive (most common X-linked disorder in men)
what is SMA? Cause?
spinal muscle atrophy caused by a loss of SMN protein (motor neuron degenerative disease that leads to muscle atrophy)
what are the type of Osteogenesis imperfecta?
Type I: null allele, loss of one of the alleles for alpha-1 chains of procollagen; less procollagen is made
Type II: generally fatal, incorporation of mutant alpha-1 chains into pro-collagen causing a dominant negative effect where only 1/4 of procollagen is functional
what is the “huntington’s chromosome”
the polyglutamine expansion seen in huntingtons disease where 36-121 CAG repeats are exist. this is over the threshold for repeats and this person will have huntingtons (10-30 repeats=no HD)
what is achondroplasia? what causes it?
dwarfism caused by a mutation (G380R) that leaves FGFR3 always active and thus always inhibits bone growth
what is swyer syndrome? cause?
males develop female sex characteristics due to the inability of SRY TF to localize to the nucleus (loss of nuclear import sequence
what are the fates of proteins translated at the rER?
rER, PM, Golgi, endosome, lysosome, exocytosed
what are the fates or proteins translated in the cytosol?
Cytosol (if no signal sequence), nucleus, mitochondria, peroxisome
how do 8-oxoguanine nucleotides form?
ROS, these nucleotides are as likely to binds with A as C
Cytoxan and platinum compounds are used as what? why?
cancer therapies b/c they stop DNA replication
Contrast HbS, HbC, HbF, HbE, HbA
HbS: sickle cell Hb (Glu6Val) HbC: abnormal Hb caused by Glu6Lys mutation; form HbC crystals HbF: fetal Hb HbE: a non-detrimental variant of Hb HbA: normal adult Hb
what is Heinz Body Hemolytic Anemia?
unstable Hb that degrades and coagulates in RBCs to form Heinze bodies. RBC hemolyze
What are the two main causes of hemolytic anemia? what is the MOA?
G6PD Deficiency: decreased NADPH and glutathione results and increased damaging ROS (bite cells)
PK deficiency: decreased ATP produced (Acanthocytes)
what are three ways in which protein folding is “helped” (prevents aggregates)
PDI, PPI, Chaperones
what are 4 diseases of protein folding?
localized amyloids (azheimers), prion disease, alpha-1-antitrypsin deficiency, systemic amyloidosis
how do high MW chaperones function?
form anfinsen cage around proteins that seqeuster them from the crowded folding environment
Specificity:
TN/TN+FP
Sensitivity:
TP/TP+FN
when do you optimize sensitivity
when you want to decrease the number of false negative; diseases that are easily spread
when do you want to optimize specificity?
when you want to decrease the number of false positives; for diseases that are deadly
what causes systemic lupus erythematosus? symptoms?
autoimmune disorder that attacks SnRNPs (used in RNA splicing). joint pain, swelling, butterfly rash on face
what causes testicular feminization
46, XY individuals that lack androgen receptors (TFs, b/c androgen diffuse through PM)
what are the 4 types of protein-membrane assoications? which are integral? peripheral? which can be removed by a change in pH or ionic composition? which must be removed by detergent?
Integral: transmembrane, membrane associated, lipid linked; removed with detergant
peripheral: protein attached; removed by change in pH or ionic composition
Cell cortex vs. glycocalyx
Cell cortex: meshwork of proteins inside the cell; stabilizes PM
Glycocalyx: layer of sugar on outer membrane that serves to lubricate cells, cell-cell recognition and protects from mechanical damage
what is the role of clatherin and adaptin?
Buzz word: vesicle budding!
Clatherin forms a protein coat around budding vesicles through its attachment to adaptin (adaptin attaches to cargo receptor which is a transmembrane protein that attaches to intracellular cargo); clatherin and adaptin help the vesicle pinch off (dynamin) and sorts cargo within the vesicle
what is the fate of clathrin and adaptin?
shed off vesicle prior to it binding to its target
other than exocytosis, when is clatherin used?
receptor mediated endocytosis
what is the role/location of Rab, tethering protein, v-snare, t-snare
Buzz word: vesicle binding to target
Rab: on vesicle
Tethering protein: on target membrane, binds Rab
V-snare (on vesicle)/t-snare (on target membrane): bring the vesicle close to the PM for fusion
what is the pathway of protein secretion starting as mRNA and ending as an extracellular protein?
mRNA–>rER–>Golgi–>PM–>outside cell
what are three modifications made to proteins in the ER?
glycosylation (dolichol), disulfide bond formation (DPI), lipid membrane anchors
release of GLUT4 is what type of endocytosis?
receptor mediated endocytosis that is triggered by insulin binding to liver or muscle cells
what is the role of M-6-P? where is it added?
M-6-P targets rER made acid hydrolases to endosomes. it is added to the acid hydrolases in the GOLGI
what type of endocytosis is the uptake of LDL cholesterol?
receptor-mediated endocytosis; clatherin dependent, allows for concentration within the cell
once in the cell, what is the fate of LDL?
LDL is just a carrier of cholesterol and thus must be degraded if cholesterol is to be used. LDL fuses with an endosome and is delivered to a lysosome where it is degraded and cholesterol freely passes out of the lysosome
what is familial hypercholesterolemia?
a lack of LDL receptors which leads to the accumulation of cholesterol within the blood (cant be taken up by cell), result in “fuzzy macrophages” (xanthoma, atherosclerosis)
what is Fick’s law?
relates to simple diffusion; Net flux=(K x Area x Concentration gradient)/distance
K: increases with hydrophobicity and decreases with size
what are the main 3 symporters? in what direction do they move substance?
Na/Cl/Na, Na/Glucose and Na/AA move both into the cell (secondary active transport)
what are the two main anti-porters? in what direction do they move substance?
Na/H and Na/Ca antiporters. move Na into the cell. Ca and Na are moved out of the cell
the movement through GLUT is what type of transport
facilitated diffusion
which ion is responsible for maintaining the resting membrane potential? why?
K. many K channels are open, few Na channels are open. the nernst equilibrium potential of K is -98 mV and the resting membrane potential is -70 mV suggesting that at the resting membrane potential K+ continuously moves out of the cell.
what is the nernst eqn? what does it tell us?
60/Z x Log([C,out]/[C,in])
give the membrane potential in which a particular ion will not move in or out of the cell based on its concentration gradient and electrical gradient.
do RBCs contain aquaporins?
yes! 200,000 per molecule. explains why they are so sensitive to changes in tonicity
Adrenergic receptors are what type of receptor? what binds them?
GPCR bound by E/NE
what does the stimulation of adrenergic receptors oft he heart do?
mostly BETA adrenergic receptors here. Increases HR and contractility
what are beta blockers used for 2? how?
Beta receptor ANTAGONISTS
- Treat high BP; decrease HR
- Treat heart failure: counters the effects of B-AR desensitization due to chronically high catecholamine levels
Gs and Gi general pathway
Gs: activates adenyl cyclase, increases cAMP, activates PKA that can phosphorylate proteins in cytosol (CFTR, muscle contractions in heart) or activate gene transcription in nucleus.
Gi: inhibits adenyl cyclase
describe GPCR desensitization (specifically B-AR)
chronically high levels of NE/E (such as those released during heart failure) can desensitize B-AR receptors.
role of GRKs
Phosphorylate and inactivate GPCR activity
how does cholera toxin work?
the G-alpha subunit of the Gs pathway is always active leading to high levels of cAMP and severe dehydration
describe the G-beta subunit signaling
Buzzwords: PKC and Calcium
G-beta activates PLC which cleaves PIP2 into IP3 and DAG. IP3 opens Ca channels in ER and DAG activates PKC. Calcium signaling and phosphorylation occurs
RTK buzzwords
Dimerization, auto-phosphorylation, SH2, GROWTH FACTORS, Ras, Insulin, AKT, MAP-Kinase cascade, PI-3K
what is the signaling pathway for insulin binding to insulin receptor
RTK!!!! PI-3K signaling pathway causes exocytosis (receptor-mediated exocytosis) of GLUT4 containing vesicles
describe NO signaling
Ach binds receptor and activates NO synthase (Argininge–>NO). NO can then diffuse into cells and activate guanyl cyclase. this creates cGMP and causes smooth muscle relaxation within blood vessels
JAK-STAT pathway: receptor type? effects?
CYTOKINE (inflammation and immunity) receptor. recruit JAKs (b/c dont have own intrinsic kinase activity) that activate STATs. STATs are TFs.
TGF-beta receptors
bind TGF-Beta ligands, phosphorylate and activate SMAD proteins that act as TFs, Ser/Thr Kinases
CFTR is a ____ gated and ____activated ion channel
ATP gated
PKA-cAMP activated
what is the number one cause of morbidity and mortality in CF?
blocked exocrine glands of the lungs due to thick mucous excretions. this causes scaring and end stage lung disease
what % CFTR function is needed to avoid symptoms?
10% only, only need to improve CFTR fxn to 10% to treat CF
Correlations in CF: which issues (pancreatic insufficiency, sweat chloride, respiratory issues) have the strongest correlation with mutation class
pancreatic: strong correlation with Class I-III mutations
Sweat chloride: moderate
lung fxn: weak
relate the presence of absence of vas deferens, positive sweat test, pulmonary infection, and PI with level of CFTR fxn (% of normal)
10>x>5: absence of vas deferens (AOVD)
5>x>4.5: AOVD, positive sweat test
4.5>x>1: AOVD, positive sweat chloride, respiratory issues
sweat chloride for CF:
60 mmol/L is CF
what is the relavence of the poly T and TG tracts in CF?
Alter pre-mRNA splicing of exon 9. 7T and 9T=normal, 5T=detrimental. TG13 and TG12 are detrimental, TG11 is normal. these variants increase risk for CF but do not cause it, more severe when cis-acting.
what percent of newborns screen positive for CF?
90%
buzzwords for autophagy
cell stress induced, degradation of organelles
what sort of things end up being targeted to a endosome (and eventually a lysosome) 3
- endocytosed materials (LDL)
- newly produced ER proteins (Acid hydrolases)
- cytsolic proteins (damaged organelles, autophagy)
buzzwords for Macroautophagy, microautophagy and chaperone-mediated autophagy
Macro: isolation membrane/autophagosome, organelles, protein aggregates
micro: autophagic tube (in the lysosome itself)
chaperone: selective, degrades long-lived proteins, LAMP2A (in lysosomal membrane translocates protein into lysosome), cytosolic Hsc70
role of mTOR
in nomral cells mTOR inhibits expression of autophagy genes. under cell stress, autophagy genes are up-regulated
statin MOA
inhibit HMGCoA reductase and lowers cholesterol (decreases production of cholesterol in the liver)
digitalis MOA
inhibits Na/K ATPase
Cholchicine MOA
binds tubuline to prevent MT polymerization
agonist
activates receptor; has affinity and intrinsic activity
antagonist
binds and prevents receptor from activating (beta blockers); affinity with no intrinsic activity
a drug is non-selective if…
if a drug interacts with one receptor but that receptor regulates multiple processes
if a drug interacts with multiple receptors
Therapeutic Index
TD50/ED50….larger value=better
Margin of Safety
MS=LD1/ED99
non-selective beta blockers 2
propanolol, sotolol
selective beta blockers
metoprolol, esmolol, atenolol
Myasthenia Gravis: Cause? Symptoms? Treatment?
Body produces antibodies against ACh. Muscle weakness (NO signaling). ACh-esterase inhibitors can be used to increase ACh
