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Molecular Foundations of Medicine > NBME Review > Flashcards

NBME Review Flashcards

1
Q

what is a telomere?

A

Nucleotides found at the end of chromosomes; contain TTAGGG sequences

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2
Q

why is telomerase needed?

A

Lagging strand has no place for RNA primer, so telomerase needed

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3
Q

how does telomerase work?

A

Telomerase recognizes telomere sequences and adds them to new DNA with RNA template -> “RNA-dependent DNA polymerase”

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4
Q

where is telomerase activity especially important?

A

cells that need controlled indefinite replications (hematopoietic stem cells, epidermis, hair follicles, intestinal mucosa —> esp affected by chemotherapy)

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5
Q

general process of base excision repair

A

damaged base removed, phosphate backbone removed, new nucleotide added

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6
Q

when does base excision repair happen

A

all phases of cell cycle

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7
Q

what is base excision repair for

A

Specific base errors recognized (ie deaminated bases, oxidized bases, open rings)

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8
Q

DNA glycosylase

A

removes damaged bases in base excision repair

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9
Q

AP endonuclease

A

attacks 5’ end and creates 3’ -OH in base excision repair

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10
Q

AP lyase

A

attacks 3’-OH end in base excision repair

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11
Q

when is nucleotide excision repair active

A

G1 phase (prior to DNA synthesis)

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12
Q

what is nucleotide excision repair for

A

For damage that involves multiple bases

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13
Q

What is nucleotide excision repair especially important for

A

repair of pyrimadine dimers caused by UV damage

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14
Q

process of nucleotide excision repair

A
  1. Endonucleases remove damaged bases
  2. DNA polymerase adds back new bases
  3. DNA ligase seals it
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15
Q

problem leading to xeroderma pigmentosa

A

defective nucleotide excision repair

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16
Q

signs and symptoms of xeroderma pigmentosa

A

extreme sensitivity to sun, dry skin, changes in pigmentation, HIGH risk of skin cancer

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17
Q

when does mismatch repair (MMR) occur

A

Occurs in S/G2 phase (after DNA synthesis)

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18
Q

what is mismatch repair (MMR) for

A

incorrectly placed bases (insertion, deletion, incorrect matches)
*KEY: the base itself is not damaged

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19
Q

mechanism is mismatch repair

A

Newly synthesized strand compared to template strand, errors removed, then resealed

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20
Q

why is mismatch repair (MMR) important

A

needed for microsatellite stability

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21
Q

what can occur if MMR is faulty

A

DNA slippage can occur at microsatellites -> insertions/deletions + possible frameshift

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22
Q

HNPCC is a problem with

A

HNPCC = hereditary non-polyposis colorectal cancer = lynch syndrome: germline mutation of MMR enzymes -> microsatellite instability and colon cancer

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23
Q

homologous end joining (HEJ)

A

for double stranded DNA damage:

Uses sister chromatids as template

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24
Q

Non-homologous end joining (NHEJ)

A

for double stranded DNA damage:
Proteins used to re-join broken ends (DNA pol lambda and mu)
KEY: no template -> highly error prone

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25
Q

defected NHEJ can lead to

A

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

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26
Q

major CFTR trafficking deficit

A

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

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27
Q

what is a dominant negative effect

A

“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”

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28
Q

ex of dominant negative effect

A

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

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29
Q

point mutation

A

1 base switched for another
Transition=purine to purine or pyrimadine to pyrimadine

Transversion = purine to pyrimadine or vice versa

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30
Q

silent mutation

A

nucleotide substitution codes for same aa, often a change in the 3rd position of codon (“wobble”)

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31
Q

nonsense mutation

A

early stop codon

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32
Q

missense mutation

A

codes for different aa

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33
Q

frameshift

A

insertion/deletion that’s not multiple of 3; can cause a early stop codon or loss of stop codon

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34
Q

mechanism of retinoblastoma formation

A

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

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35
Q

two-hit origin of cancer

A

mutation of tumor suppressor genes
Heterozygous mutation -> no disease

Loss of heterozygosity

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36
Q

huntington gene abnormality

A

HTT gene located at 4p16.3; CAG expansion in Exon 1

CAG codes for glutamine (Q) -> PolyQ tract

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37
Q

hypothesized cause of expansion in huntington

A

Meiotic instability in sperm -> unequal crossing over

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38
Q

huntington protein has high expression in

A

testes and brain

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39
Q

function of huntington protein

A

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

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40
Q

CAG expansion in huntington leads to

A

aggregation of mutant protein into inclusion bodies

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41
Q

inheritance of huntington

A

AD

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42
Q

symptoms in huntington caused by

A

degeneration in basal ganglia (striatum)

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43
Q

presentation of huntington

A

Characterized by dementia, chorea, ataxia, and dysarthria

Death usually 10-20 years after diagnosis

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44
Q

results of meiosis I

A

“Reductive division” -> diploid to halpoid

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45
Q

results of meiosis II

A

Chromatids separate -> 4 daughter cells (haploid)

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46
Q

spermatogenesis

A

Begins at puberty
Spermatogonium (2n) -> Mitosis -> 1° spermatocyte (2n) -> meiosis I -> 2° spermatocyte (1n) -> meiosis II -> spermatid (1n) -> spermiogenesis -> spermatozoa

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47
Q

oogenesis

A

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

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48
Q

meiotic NDJ

A

Failure of chromosomes to separate; most common cause of aneuploidy

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49
Q

Meiosis I NDJ

A

homologous chromosomes fail to separate -> games have chromosomes from both parents

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50
Q

Meiosis II NDJ

A

sister chromatids fail to separate (ie XXY males)

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51
Q

maternal NDJ

A

common cause of trisomy; higher risk because meiosis 1 is so drawn out

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52
Q

mitochondrial diseases typically refer to defects in

A

aerobic metabolism (electron transport chain)

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53
Q

how many proteins encoded by mtDNA

A

13 polypeptide protein subunits

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54
Q

systems most affected by mitochondrial diseases

A

neurologic, muscular, cardiac

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55
Q

heteroplasmy

A

Mitochondria have multiple copies of mtDNA

Cells have multiple mitochondria
Heteroplasmy occurs when there is a mixture of normal and abnormal

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56
Q

implication of heteroplasm

A

uncertain chance of passing on mitochondrial diseases from mother

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57
Q

chimerism

A

2 genomes present in 1 individual -> usually result of fusion of 2 zygotes

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58
Q

mosaicism typically occurs

A

as result of a post-fertilization mitotic error

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59
Q

somatic mosaicism

A

in the body, usually develops post-conception

ie Congenital hyperpigmentation- male with mental retardation and swirling pigmentation. Diagnosed by chromosome study of skin cells

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60
Q

germline mosaicism

A

confined to germ cells. The individual will not have any symptoms, but may have multiple offspring with a mutation frequently thought of as sporadic

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61
Q

inheritance of CF (and chromosome)

A

AR, chromosome 7

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62
Q

mutations in CFTR gene cause

A

abnormal chloride transport -> thick mucous due to lack of water equilibrium

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63
Q

PKU inheritance pattern

A

AR

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64
Q

presentation of PKU

A

Normal neonate, dev delay beginning around 3-4 months

65
Q

problem in PKU

A

Phenylalanine hydroxylase (PAH) deficiency -> phenylalanine cannot be converted to tyrosine

66
Q

inheritance of marfan syndrome

A

AD, 25% are de novo

highly penetrant

67
Q

gene and protein in marfan

A

FBN-1 gene -> fibrillin protein

68
Q

associated problems with marfan

A

dilated aortic root
ectopia lentis
skeletal changes
dural ectasia

69
Q

hemophilia A

A

XR

caused by reduced factor VIII -> excessive bleeding

70
Q

Tay-sachs inheritance

A

AR

71
Q

what is tay sachs

A

Neurodegenerative lysosomal storage disorder

72
Q

mutant enzyme in tay-sachs

A

β-Hexosaminidase (A isoenzyme) -> critical role in brain and spinal cord; buildup of fatty substance GM2 ganglioside

73
Q

clinical features in tay-sachs

A

hypotonia, spasticity, seizures, blindness

74
Q

hardy weinberg equations

A

P+Q=1

P^2 +2PQ + Q^2 = 1

75
Q

hardy weiberg assumptions

A 
Large population
Random mating
No effect of recurrent mutation
No selection against any phenotype
No migration
Autosomal locus
76
Q

exceptions to hardy weinberg

A

Nonrandom mating: stratification, assortative mating, consanguinity

Small populations: inbreeding, genetic drift, founder effect

77
Q

what is klinefelter syndrome

A

A male with 1 or more extra X chromosomes; 1/1,000 males

78
Q

presentation of klinefelter syndrome

A

Tall with long limbs, small firm testes with hyalinization of seminiferous tubules and azospermia

Gynecomastia: breast cancer risk = women

79
Q

causes of klinefelter (XXY)

A

maternal and paternal NDJ are equal

80
Q

most common trisomy

A

16, but never seen in liveborns

81
Q

mechanism of trisomy

A

NDJ in mother or father results in trisomy (fusion of a 2n gamete with a 1n gamete)

82
Q

trisomy 21, 18, and 13 and XXX most commonly caused by

A

maternal MI NDJ

83
Q

cause of XXY

A

equally caused by maternal and paternal NDJ

84
Q

45,x caused by

A

mainly by paternal NDJ

85
Q

importance of X-chromosome inactivation

A

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

86
Q

inheritance of achondroplasia

A

AD
complete penetrance
80% de novo

87
Q

genetic abnormality in achondroplasia

A

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

88
Q

presentation of achondroplasia

A

Short limbed (rhizomelic), macrocephaly, skeletal and CNS complications, normal IQ, clinically and genetically homogeneous

89
Q

complications in achondroplasia

A

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

90
Q

most common pathogenic variant in achondroplasia

A

G1138A (98%)

91
Q

features of prader willi syndrome

A

Hypthalamic dysfunction -> lack of satiety -> obesity

Hypogonadotropic hypogonadism

Growth hormone deficiency -> short stature and diminished muscle
Cognitive/behavioral impairment

92
Q

cause in prader willi

A

lack of expression of paternal genes at 15q11.13

93
Q

mechanism frequencies in prader willi

A

microdeletion of on paternal 15q11.13 (70%), maternal UPD (25%), imprinting defect on paternal 15q11.13 (5%)

94
Q

key of prader willi in infant

A

hypotonia, feeding problems, cryptorchidism, may be hypopigmented

95
Q

key of prader willi in children

A

obesity, oppositional behaviors, learning problems, short stature

96
Q

key of prader willi in adults

A

type 2 DM, obstructive sleep apnea, hypogonadism

97
Q

fragile x inheritance

A

X-linked dominant

98
Q

genetic abnormality in fragile x

A

Expansion of CGG in 5’ UTR of the FMR-1 gene that encodes FMRP

99
Q

FMRP implicated in

A

dendritic spine maturation, synapse formation, and synaptic plasticity

100
Q

high FMRP expression in

A

brain and testes

101
Q

presentation of fragile x

A

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

102
Q

associated problems with fragile x

A

Can have mitral valve prolapse, HTN, seizures, strabismus

103
Q

mechanism of genomic imprinting

A

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

104
Q

genetic testing can lead to (counseling)

A

detection of false paternity
Stigmatization - including survivor guilt

Loss of employment or insurance
Psychological harm

105
Q

therapeutic index formula

A

TI=TD50/ED50

106
Q

what is bioavailability (F)

A

the fraction or percent of unchanged drug that reaches systemic circulation from a site of administration

107
Q

calculate bioavailability (F) from graph

A

graph concentration vs. time for 2 methods of administration (ie IV and PO) and compare the areas under their curves

F=(AUCoral/AUCiv)

108
Q

factors that affect absorption of a drug

A

bioavailability and first-pass metabolism

109
Q

factors that determine bioavailability

A

physiology (ie first-pass metabolism), physicochemical (ie drug ionization), and biopharmaceutical (ie table dissolution, particle size)

110
Q

majority of drugs use what mechanism of permeation

A

passive diffusion through cell membrane lipid

111
Q

key relationship in passive diffusion through cell membrane lipid

A

rate of absorption ∝ unionized [drug] at site of admin

112
Q

henderson hasselbach

A

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)

113
Q

key relationship in carrier mediated transport (active transport of facilitated diffusion)

A

RATE OF ABSORPTION ∝ DRUG CONC ONLY WHEN CARRIER NOT SATURATED

114
Q

carrier mediated transport can be affected by

A

competitive and noncompetitive inhibition

115
Q

drug distribution

A

only unbound drug can penetrate cell membranes

Many drugs bind to albumin, basic drugs bind to globulins, binding usually reversible, nonselective, and competitive

116
Q

phase 1 metabolism

A

introduce or unmask polar functional group (-OH, -NH2, -SH); if sufficiently polar, will be excreted, if not -> phase II

117
Q

phase II metabolism

A

conjugation and synthetic reaction addition of acid or amino acid ie Glucuronidation

enterohepatic recycling

118
Q

partition coefficient directly proportional to

A

amount that gets absorbed

119
Q

mixed function oxidases (MFOs)

A

involved in phase I metabolism
AKA monooxygenases require reducing agent and molecular oxygen
(NADPH is reducing agent)

120
Q

hepatic sites of metabolism

A

Microsomal: vesicles enriched in ER membranes; contain enzymes catalyzing oxidation reactions and glucorinide conjugation

Non-miccrosomal: primarily in liver

121
Q

2 key microsomal enzymes

A

NADPH-cytochrome P450 recutase

cytochrome P450

122
Q

zero order drug elimination

A

a constant amount eliminated per time

123
Q

first order drug elimination

A

a constant fraction (or percentage) of drug is eliminated per unit of time

dD/dt= -Ke * D

124
Q

oral drug administration

A

(PO)

most convenient; may have significant 1st pass metabolism

125
Q

IV drug administration

A

100% bioavailability; most rapid onset of action

126
Q

IM drug administation

A

may be painful

127
Q

SC drug administrtion

A

smaller volumes than IV; may be painful

128
Q

rectal drug administration

A

less first-pass effect than oral

129
Q

inhalation drug administration

A

often rapid onset of action

130
Q

sublingual drug administration

A

rapid onset; minimal first-pass effect

131
Q

intrathecal drug administration

A

bypass blood-CSF barrier and blood-brain barrier; risks of infection & HA

132
Q

transdermal drug administration

A

slow absorption; longer duration of action; lack of first-pass effect

133
Q

equation for volume of distribution

A

Vd= D/C, where D is amount administered and C is concentration of drug

134
Q

what is volume of distribution

A

(Vd) = volume of fluid that would be needed to contain the administered amount of drug at the concentration measured in plasma

135
Q

calculate dose

A

D=Vd*C

If bioavaliability not 100%, D = (Vd * C)/F

136
Q

calculate drug clearance rate from blood

A

(CL=Vd * Ke)

Note: only unbound (free) drug can be cleared by an organ

137
Q

steady state drug clearance proportional

A

Css ∝ 1/CL

138
Q

first order clearance kinetics

A

Occurs at relatively low substrate conc.

Generally, when V is less than or equal to 10% Vmax

V∝ [D]

139
Q

zero order clearance kinetics

A

Occurs when [D] is relatively high

V = Vmax

140
Q

compare effectiveness of drugs

A

Therapeutic index = TD50 / ED50

Margin of safety = TD1/ED99

141
Q

calculate drug loading dose

A

Loading dose = (Vd * C)/ F

142
Q

calculate maintenance dose

A

Maintenance dose = (CL * Css)/ F

143
Q

how to maintain steady state

A

drug administration = drug elimination = CL * CSS

144
Q

agonist

A

a drug that mimics the effects of the endogenous ligand for a receptor

intrinsic activity >0friedreich

145
Q

antagonist

A

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

146
Q

friedreich’s ataxia inheritance

A

AR

147
Q

genetic defect in friedreich’s ataxia

A

GAA repeat in first intron on FXN gene, chromsome 9

148
Q

GAA repeat in friedreich’s ataxia causes

A

transcriptional repression -> less frataxin

149
Q

compound heterozygotes in friedreich’s ataxia

A

4%

expansion on one allele and other mutation of FXN in other allele

150
Q

frataxin protein function

A

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

151
Q

iron buildup in friedreich’s ataxia causes

A

spinal cord becomes thinner and nerves lose part of their myelin sheath

152
Q

signs and symptoms of friedreich’s ataxia

A

muscle weakness in arms and legs, loss of coordination, vision impairement, hearing impairment, slurred speech, scoliosis, pes cavus, diabetes, hypertrophic cardiomyopathy, afib->tachycardia

153
Q

steroid receptor function

A

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

154
Q

histone structure

A

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

155
Q

HAT=histone acetyltransferase

A

Acetyl groups can be added to lysine residues on histone -> relaxes chromatin -> transcription

156
Q

HDAC=histone deacetylase

A

If acetyl groups are removed -> condenses chromatin -> blocks transcription

157
Q

insulin receptor signaling pathway

A

Insulin uses receptor tyrosine kinase (RTKs)

Insulin binds -> RTK autophosphorylates -> IRS-1 is phosphorylated -> gene transcription

No second messenger

158
Q

growth factor signaling pathway

A

Growth factors use RTKs

GF binds RTK -> dimerization -> autophosphorylation -> Ras -> Raf -> MEK -> ERK -> TFs

GTP->GDP as ras phosphorylates raf

Molecular Foundations of Medicine (21 decks)

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