NBME Review Flashcards
what is a telomere?
Nucleotides found at the end of chromosomes; contain TTAGGG sequences
why is telomerase needed?
Lagging strand has no place for RNA primer, so telomerase needed
how does telomerase work?
Telomerase recognizes telomere sequences and adds them to new DNA with RNA template -> “RNA-dependent DNA polymerase”
where is telomerase activity especially important?
cells that need controlled indefinite replications (hematopoietic stem cells, epidermis, hair follicles, intestinal mucosa —> esp affected by chemotherapy)
general process of base excision repair
damaged base removed, phosphate backbone removed, new nucleotide added
when does base excision repair happen
all phases of cell cycle
what is base excision repair for
Specific base errors recognized (ie deaminated bases, oxidized bases, open rings)
DNA glycosylase
removes damaged bases in base excision repair
AP endonuclease
attacks 5’ end and creates 3’ -OH in base excision repair
AP lyase
attacks 3’-OH end in base excision repair
when is nucleotide excision repair active
G1 phase (prior to DNA synthesis)
what is nucleotide excision repair for
For damage that involves multiple bases
What is nucleotide excision repair especially important for
repair of pyrimadine dimers caused by UV damage
process of nucleotide excision repair
- Endonucleases remove damaged bases
- DNA polymerase adds back new bases
- DNA ligase seals it
problem leading to xeroderma pigmentosa
defective nucleotide excision repair
signs and symptoms of xeroderma pigmentosa
extreme sensitivity to sun, dry skin, changes in pigmentation, HIGH risk of skin cancer
when does mismatch repair (MMR) occur
Occurs in S/G2 phase (after DNA synthesis)
what is mismatch repair (MMR) for
incorrectly placed bases (insertion, deletion, incorrect matches)
*KEY: the base itself is not damaged
mechanism is mismatch repair
Newly synthesized strand compared to template strand, errors removed, then resealed
why is mismatch repair (MMR) important
needed for microsatellite stability
what can occur if MMR is faulty
DNA slippage can occur at microsatellites -> insertions/deletions + possible frameshift
HNPCC is a problem with
HNPCC = hereditary non-polyposis colorectal cancer = lynch syndrome: germline mutation of MMR enzymes -> microsatellite instability and colon cancer
homologous end joining (HEJ)
for double stranded DNA damage:
Uses sister chromatids as template
Non-homologous end joining (NHEJ)
for double stranded DNA damage:
Proteins used to re-join broken ends (DNA pol lambda and mu)
KEY: no template -> highly error prone
defected NHEJ can lead to
Ataxia telangiectasia: ATM gene on chromosome 11, DNA sensitive to ionizing radiation. CNS, skin, immune system affected. Usually 1st year healthy then slow dev, progressive motor coordination problems. High risk cancer
major CFTR trafficking deficit
In the ΔF508 mutation, the CFTR protein is still made, just laking the 508th a.a. (Phenylalanine)
It is still a functional protein, but is misfolded in ER which causes ubiquination (rather than transport to golgi) and then degredation by proteasomes
what is a dominant negative effect
“A mutation whose gene product adversely affects the normal, wild-type gene product within the same cell. Usually occurs if product can still interact with the same elements as the wild-type product, but block some aspect of its functions”
ex of dominant negative effect
Nonsense mediated decay -> quality control mechanism that eliminates mRNA transcripts that have premature termination codons (PTCs)
Beta-thalassemia depends on NMD pathway; many mutations can alter splicing and/or result in PTC -> triggering mRNA decay and loss of protein
Other mutations are NMD resistant and result in truncated products that act in dominant negative manner
point mutation
1 base switched for another
Transition=purine to purine or pyrimadine to pyrimadine
Transversion = purine to pyrimadine or vice versa
silent mutation
nucleotide substitution codes for same aa, often a change in the 3rd position of codon (“wobble”)
nonsense mutation
early stop codon
missense mutation
codes for different aa
frameshift
insertion/deletion that’s not multiple of 3; can cause a early stop codon or loss of stop codon
mechanism of retinoblastoma formation
Mutation in rb protein, which normally binds to E2F until rb is phosporylated
Phosphorylation of rb by G1-S-CDK releases inhibition
rb regulates cell growth -> “tumor suppressor”
Abnormal rb -> unregulated cell growth via E2F
two-hit origin of cancer
mutation of tumor suppressor genes
Heterozygous mutation -> no disease
Loss of heterozygosity
huntington gene abnormality
HTT gene located at 4p16.3; CAG expansion in Exon 1
CAG codes for glutamine (Q) -> PolyQ tract
hypothesized cause of expansion in huntington
Meiotic instability in sperm -> unequal crossing over
huntington protein has high expression in
testes and brain
function of huntington protein
Found in nucleus and cytoplasm and regulates intracellular transport of many proteins, including shuttling TFs in and out of nucleus or sequestering them
Required for normal embryonic dev and neurogenesis
CAG expansion in huntington leads to
aggregation of mutant protein into inclusion bodies
inheritance of huntington
AD
symptoms in huntington caused by
degeneration in basal ganglia (striatum)
presentation of huntington
Characterized by dementia, chorea, ataxia, and dysarthria
Death usually 10-20 years after diagnosis
results of meiosis I
“Reductive division” -> diploid to halpoid
results of meiosis II
Chromatids separate -> 4 daughter cells (haploid)
spermatogenesis
Begins at puberty
Spermatogonium (2n) -> Mitosis -> 1° spermatocyte (2n) -> meiosis I -> 2° spermatocyte (1n) -> meiosis II -> spermatid (1n) -> spermiogenesis -> spermatozoa
oogenesis
1° oocytes (2n) formed in utero -> arrested in prophase I
At puberty, 1° oocytes begin completing meiosis I each cycle -> 2° oocytes (1n) and polar bodies
2° oocytes arrested in metaphase II until fertilization
meiotic NDJ
Failure of chromosomes to separate; most common cause of aneuploidy
Meiosis I NDJ
homologous chromosomes fail to separate -> games have chromosomes from both parents
Meiosis II NDJ
sister chromatids fail to separate (ie XXY males)
maternal NDJ
common cause of trisomy; higher risk because meiosis 1 is so drawn out
mitochondrial diseases typically refer to defects in
aerobic metabolism (electron transport chain)
how many proteins encoded by mtDNA
13 polypeptide protein subunits
systems most affected by mitochondrial diseases
neurologic, muscular, cardiac
heteroplasmy
Mitochondria have multiple copies of mtDNA
Cells have multiple mitochondria
Heteroplasmy occurs when there is a mixture of normal and abnormal
implication of heteroplasm
uncertain chance of passing on mitochondrial diseases from mother
chimerism
2 genomes present in 1 individual -> usually result of fusion of 2 zygotes
mosaicism typically occurs
as result of a post-fertilization mitotic error
somatic mosaicism
in the body, usually develops post-conception
ie Congenital hyperpigmentation- male with mental retardation and swirling pigmentation. Diagnosed by chromosome study of skin cells
germline mosaicism
confined to germ cells. The individual will not have any symptoms, but may have multiple offspring with a mutation frequently thought of as sporadic
inheritance of CF (and chromosome)
AR, chromosome 7
mutations in CFTR gene cause
abnormal chloride transport -> thick mucous due to lack of water equilibrium
PKU inheritance pattern
AR
presentation of PKU
Normal neonate, dev delay beginning around 3-4 months
problem in PKU
Phenylalanine hydroxylase (PAH) deficiency -> phenylalanine cannot be converted to tyrosine
inheritance of marfan syndrome
AD, 25% are de novo
highly penetrant
gene and protein in marfan
FBN-1 gene -> fibrillin protein
associated problems with marfan
dilated aortic root
ectopia lentis
skeletal changes
dural ectasia
hemophilia A
XR
caused by reduced factor VIII -> excessive bleeding
Tay-sachs inheritance
AR
what is tay sachs
Neurodegenerative lysosomal storage disorder
mutant enzyme in tay-sachs
β-Hexosaminidase (A isoenzyme) -> critical role in brain and spinal cord; buildup of fatty substance GM2 ganglioside
clinical features in tay-sachs
hypotonia, spasticity, seizures, blindness
hardy weinberg equations
P+Q=1
P^2 +2PQ + Q^2 = 1
hardy weiberg assumptions
Large population Random mating No effect of recurrent mutation No selection against any phenotype No migration Autosomal locus
exceptions to hardy weinberg
Nonrandom mating: stratification, assortative mating, consanguinity
Small populations: inbreeding, genetic drift, founder effect
what is klinefelter syndrome
A male with 1 or more extra X chromosomes; 1/1,000 males
presentation of klinefelter syndrome
Tall with long limbs, small firm testes with hyalinization of seminiferous tubules and azospermia
Gynecomastia: breast cancer risk = women
causes of klinefelter (XXY)
maternal and paternal NDJ are equal
most common trisomy
16, but never seen in liveborns
mechanism of trisomy
NDJ in mother or father results in trisomy (fusion of a 2n gamete with a 1n gamete)
trisomy 21, 18, and 13 and XXX most commonly caused by
maternal MI NDJ
cause of XXY
equally caused by maternal and paternal NDJ
45,x caused by
mainly by paternal NDJ
importance of X-chromosome inactivation
AKA lyonization
Random from cell to cell which X chromosome will be inactivated (“functional mosaicism”)
Skewed lyonization can result in females having x-linked recessive expression
inheritance of achondroplasia
AD
complete penetrance
80% de novo
genetic abnormality in achondroplasia
Mutations in the fibroblast growth factor receptor (FGFR) 3 gene
FGFR3 is negative regulator of bone growth -> mutation activates the gene -> inhibiting bone growth -> gain of function mutation
presentation of achondroplasia
Short limbed (rhizomelic), macrocephaly, skeletal and CNS complications, normal IQ, clinically and genetically homogeneous
complications in achondroplasia
Compression of spinal cord and/or upper airway obstruction increaces risk of death in infancy
7-8% of infants die from obstructive or central apnea, which can be due to brain stem compression
most common pathogenic variant in achondroplasia
G1138A (98%)
features of prader willi syndrome
Hypthalamic dysfunction -> lack of satiety -> obesity
Hypogonadotropic hypogonadism
Growth hormone deficiency -> short stature and diminished muscle
Cognitive/behavioral impairment
cause in prader willi
lack of expression of paternal genes at 15q11.13
mechanism frequencies in prader willi
microdeletion of on paternal 15q11.13 (70%), maternal UPD (25%), imprinting defect on paternal 15q11.13 (5%)
key of prader willi in infant
hypotonia, feeding problems, cryptorchidism, may be hypopigmented
key of prader willi in children
obesity, oppositional behaviors, learning problems, short stature
key of prader willi in adults
type 2 DM, obstructive sleep apnea, hypogonadism
fragile x inheritance
X-linked dominant
genetic abnormality in fragile x
Expansion of CGG in 5’ UTR of the FMR-1 gene that encodes FMRP
FMRP implicated in
dendritic spine maturation, synapse formation, and synaptic plasticity
high FMRP expression in
brain and testes
presentation of fragile x
Males have characteristic appearance: large head, long face, prominent forehead and chin, protruding ears
Associated with CT findings -> joint laxity and large testes after puberty, hypotonia
Behavioral abnormalities common
associated problems with fragile x
Can have mitral valve prolapse, HTN, seizures, strabismus
mechanism of genomic imprinting
Parent-of-origin difference in gene expression due to epigenetic modification
Usually done by methylation or changes in chromatin structure
Most imprints erased and restored each new generation
genetic testing can lead to (counseling)
detection of false paternity
Stigmatization - including survivor guilt
Loss of employment or insurance
Psychological harm
therapeutic index formula
TI=TD50/ED50
what is bioavailability (F)
the fraction or percent of unchanged drug that reaches systemic circulation from a site of administration
calculate bioavailability (F) from graph
graph concentration vs. time for 2 methods of administration (ie IV and PO) and compare the areas under their curves
F=(AUCoral/AUCiv)
factors that affect absorption of a drug
bioavailability and first-pass metabolism
factors that determine bioavailability
physiology (ie first-pass metabolism), physicochemical (ie drug ionization), and biopharmaceutical (ie table dissolution, particle size)
majority of drugs use what mechanism of permeation
passive diffusion through cell membrane lipid
key relationship in passive diffusion through cell membrane lipid
rate of absorption ∝ unionized [drug] at site of admin
henderson hasselbach
HAH+ + A-
BH+ H+ + B
pKa - pH = log (protonated/unprotonated)
pKa is dissociation constant
pH is the pH of surroundings
When pHpKA, unprotonated forms predominate (A- and B)
key relationship in carrier mediated transport (active transport of facilitated diffusion)
RATE OF ABSORPTION ∝ DRUG CONC ONLY WHEN CARRIER NOT SATURATED
carrier mediated transport can be affected by
competitive and noncompetitive inhibition
drug distribution
only unbound drug can penetrate cell membranes
Many drugs bind to albumin, basic drugs bind to globulins, binding usually reversible, nonselective, and competitive
phase 1 metabolism
introduce or unmask polar functional group (-OH, -NH2, -SH); if sufficiently polar, will be excreted, if not -> phase II
phase II metabolism
conjugation and synthetic reaction addition of acid or amino acid ie Glucuronidation
enterohepatic recycling
partition coefficient directly proportional to
amount that gets absorbed
mixed function oxidases (MFOs)
involved in phase I metabolism
AKA monooxygenases require reducing agent and molecular oxygen
(NADPH is reducing agent)
hepatic sites of metabolism
Microsomal: vesicles enriched in ER membranes; contain enzymes catalyzing oxidation reactions and glucorinide conjugation
Non-miccrosomal: primarily in liver
2 key microsomal enzymes
NADPH-cytochrome P450 recutase
cytochrome P450
zero order drug elimination
a constant amount eliminated per time
first order drug elimination
a constant fraction (or percentage) of drug is eliminated per unit of time
dD/dt= -Ke * D
oral drug administration
(PO)
most convenient; may have significant 1st pass metabolism
IV drug administration
100% bioavailability; most rapid onset of action
IM drug administation
may be painful
SC drug administrtion
smaller volumes than IV; may be painful
rectal drug administration
less first-pass effect than oral
inhalation drug administration
often rapid onset of action
sublingual drug administration
rapid onset; minimal first-pass effect
intrathecal drug administration
bypass blood-CSF barrier and blood-brain barrier; risks of infection & HA
transdermal drug administration
slow absorption; longer duration of action; lack of first-pass effect
equation for volume of distribution
Vd= D/C, where D is amount administered and C is concentration of drug
what is volume of distribution
(Vd) = volume of fluid that would be needed to contain the administered amount of drug at the concentration measured in plasma
calculate dose
D=Vd*C
If bioavaliability not 100%, D = (Vd * C)/F
calculate drug clearance rate from blood
(CL=Vd * Ke)
Note: only unbound (free) drug can be cleared by an organ
steady state drug clearance proportional
Css ∝ 1/CL
first order clearance kinetics
Occurs at relatively low substrate conc.
Generally, when V is less than or equal to 10% Vmax
V∝ [D]
zero order clearance kinetics
Occurs when [D] is relatively high
V = Vmax
compare effectiveness of drugs
Therapeutic index = TD50 / ED50
Margin of safety = TD1/ED99
calculate drug loading dose
Loading dose = (Vd * C)/ F
calculate maintenance dose
Maintenance dose = (CL * Css)/ F
how to maintain steady state
drug administration = drug elimination = CL * CSS
agonist
a drug that mimics the effects of the endogenous ligand for a receptor
intrinsic activity >0friedreich
antagonist
a drug, which does not itself have intrinsic activity, but which interferes with the binding of the endogenous ligand (or an agonist) to a receptor
friedreich’s ataxia inheritance
AR
genetic defect in friedreich’s ataxia
GAA repeat in first intron on FXN gene, chromsome 9
GAA repeat in friedreich’s ataxia causes
transcriptional repression -> less frataxin
compound heterozygotes in friedreich’s ataxia
4%
expansion on one allele and other mutation of FXN in other allele
frataxin protein function
removes iron in the cytoplasm and around mitochondria
iron buildup causes free radical damage (oxidative stress) to mitochondrial membrane, esp affecting nerve and muscle cells
iron buildup in friedreich’s ataxia causes
spinal cord becomes thinner and nerves lose part of their myelin sheath
signs and symptoms of friedreich’s ataxia
muscle weakness in arms and legs, loss of coordination, vision impairement, hearing impairment, slurred speech, scoliosis, pes cavus, diabetes, hypertrophic cardiomyopathy, afib->tachycardia
steroid receptor function
Steroid hormones are lipid soluble/intracellular and can cross plasma membrane
Receptors are in the cytoplasm or nucleus
These hormones travel through blood bound to a protein
histone structure
H2A, H2B, H3 and H4 make up an octamer that DNA wraps around
H1 special histone outside the nucleosome core; larger and more basic; ties “beads on string” together
HAT=histone acetyltransferase
Acetyl groups can be added to lysine residues on histone -> relaxes chromatin -> transcription
HDAC=histone deacetylase
If acetyl groups are removed -> condenses chromatin -> blocks transcription
insulin receptor signaling pathway
Insulin uses receptor tyrosine kinase (RTKs)
Insulin binds -> RTK autophosphorylates -> IRS-1 is phosphorylated -> gene transcription
No second messenger
growth factor signaling pathway
Growth factors use RTKs
GF binds RTK -> dimerization -> autophosphorylation -> Ras -> Raf -> MEK -> ERK -> TFs
GTP->GDP as ras phosphorylates raf
