UWORLD Second Pass Notes

Genetics

Fragile X Syndrome
o FMR1 gene normally has 5-55 CGG repeats
o More CGG repeats (>200) leads to FMR1 gene hypermethylation
which inactivates FMR1. Inactivated gene will not make the protein
needed to neuronal development
o Use southern blot to measure degree of methylation and determine #
of CGG repeats
X-inactivation
o After fertilization, every cell in a female will randomly inactivate an x.
o The process of X inactivation converts the inactive x chromosome in
to condensed heterochromatin which, under the microscope, looks
like a compact body at the periphery of the nucleus (Barr Body)
o Heterochromatin is heavily methylated DNA and deacetylated
histones which causes it to have a low level of transcriptional activity
o Small amounts of genes on the inactivated X will remain
transcriptionally active. B/c of this, having more than 2 X
chromosomes manifests clinically because of gene-dosage effect
(Turner syndrome 45XO and Kleinefelter 47XXY)
Linkage disequilibrium
o Two genetic loci are in linkage disequilibrium when their alleles are
inherited together. Often due to the physical proximity of the genes on
the same chromosome
o To estimate probability of 2 alleles appearing together, multiply their
frequencies together. If the observed frequency is greater than the
calculated one than the population is in linkage disequilibrium
Turner Syndrome
o Female: ovarian dysgenesis. Ovaries appear underdeveloped and
atrophic with fat streaks (ovarian dysgenesis)
Blots
o Southern: analyze and identify DNA fragments
o Western: analyze and identify proteins
o Northern: analyze and identify RNA
o Southwestern: analyze and identify DNA bound proteins
o *SNOW
o *DROP
Beta Thalassemia
o Intermediate
Caused by an inherited Beta globin gene mutation in the Kozak
sequence (a consensus sequence that helps to start
translation). If this sequence is mutated, translation will not
occur on the beta globin gene and you will not get enough Beta
 globin chains for hemoglobin = hypochromic microcytic
anemia
Epidemics and Pandemics
o Influenza epidemics and pandemics are caused by reassortment of the
RNA segments coding for hemagglutinin or neuraminidase proteins
(major antigenic shifts). Allows a swine or bird flu to be transmitted
to humans and then passed from human to human
Homeobox sequence (HOX gene)
o A highly conserved DNA sequence 180 nucleotides in length
o Homeobox genes encode DNA-binding transcription factors that play
an important role in the segmental organization of the embryo along
the cranio-caudal axis
Down Syndrome
o Duodenal atresia: most common GI abnormality in Downs. Failure of
the duodenum to recanalize in early gestation. Present during first
few days of life with emesis and double bubble sign (represents
the dilated stomach and proximal duodenum. They dilate because
they are above the blockage [the distal duodenum is completely
closed off=blockage).
o Results from nondisjunction of maternal Ch. 21 during Meiosis 1
Somatic Vs. Germline
o Somatic
Affects the cells that form the body causing disease
manifestations to develop in affected pts
Often seen somatic mosaicism in turners syndrome where
some cells are 45X and others are 46XX
Affect cells that give rise to gametes allowing an affected gene
to pass to the offspring.
Autosomal Recessive Math
o If an unaffected parent has an affected sibling then the chance that the
unaffected parent is a carrier is 2/3 (grandparents would have had to
have been Rr and Rr. So the punnent square for the parent gives RR,
Rr, Rr, and rr. We know that the parent is not affected so only RR, Rr,
and Rr remain as likely possibilities for the parents genotype. So the
chance that the parent is a carrier is 2 [Rr and Rr] out of 3 [Rr,Rr, RR]
possibilities so 2/3.) The chance of passing the trait to her child would
be 2/3 (chance she is a carrier) * (likelihood that she will pass the r
gene and not the R gene) so (2/3)*(1/2) = 1/3
Frameshift mutation
o Results when a number of bases that is not divisible by 3 is added or
deleted from the coding region of a gene. The mutation will alter the
reading frame resulting in creating of nonfunctional proteins
o Cystic Fibrosis is 70% of the time a frameshift mutation where a base
is removed leading to PHE not being coded for and the result is
phenylalanine is not produced.
 In frame mutation
o A complete codon (3 amino acids) is removed. Does not affect the
reading frame of subsequent codons
Missense mutation
o A single base is replaced by a different AA. The new sequence codes
for a different codon than the old sequence would have coded for
Nonsense mutation
o A single base is replaced by a different AA. The new 3 base sequence
codes for a stop codon
Silent mutation
o Would not alter a patients phenotype. Occur in both coding and non-
coding regions
Histones
o Core made up of 8 histone proteins (2 each of H2A, H2B, H3, and H4)
o H1 is located outside of the histone core. H1 histones bind the linker
segments of DNA that lie between nucleosomes (a ball of H2, H3, H4
that DNA wraps around) and facilitate packaging of nucleosomes in to
more compact structures
o DNA associated with histones appears like beads on a string
Genetic Shift Viruses
o Viruses with segmented genomes (orthomyxoviruses, reoviruses,
bunyavirues, rotaviruses, Influenza A and arenaviruses) are capable of
genetic shift through reassortment. Reassortment (genetic shift)
involves exchange of entire genomic segments, a far more dramatic
process than the point mutations responsible for genetic drift
Robertsonian Translocation
Hardy Weinberg
o Carrier Frequency = percent chance of being a carrier of a specific
allele (not a pair)
p= frequency of the dominant allele
q= frequency of recessive allele
o Population frequency
p^2= predicted frequency of homozygous dominant in a
population
q^2= predicted frequency of homozygous recessive in a
population
2pq= predicted frequency of heterozygous in a population
Cystic Fibrosis
o Males have absent vas deferens
o Most common gene mutation is a 3 base pair deletion of phenyalanine
at amino acid position 508 (delta F508 mutation). This mutation
causes impaired post translational processing (improper folding and
glycosylation) of CFTR, which is detected by the endoplasmic
reticulum. As a result, the abnormal protein is target for proteaosomal
 degradation, preventing it from reaching the cell surface. There will
be a complete absence of the CFTR protein on the cell surface.
Lumacaftor (drug) can partially correct this folding defect
leading to CFTR expression
o PCP
AKA. Phencyclidine
A N-methyl-D-aspartate (NMDA) receptor antagonist with
lesser effects on the reuptake inhibition of dopamine,
norepinephrine, and serotonin. Has dissociative and anesthetic
effects as well as psychosis and sever agitation leading to
violent trauma.
Ataxia, horizontal and vertical nystagmus and delirium also
present
Most likely cause of death is due to trauma from the combative
behavior
o Antipsychotic side effects
More common in typical antipsycotics and less common in
atypical
Extrapyramidal Side effects
*treat using: benztropine, diphenhydramine, or
benzodiazepines
*Results from D2 blockade in the Nigrostriatal pathway
Acute Dystonic reaction: sudden onset muscle
contractions
Akathisia: restlessness and inability to sit still (ex.
Restless legs)
Drug induced Parkinsonism: tremor, cogwheel ridgidity,
bradykinesia, masked facies,
Tardive dyskinesia
Involuntary movements of mouth (lip smacking,
sticking out tongue)
Neuroleptic malignant syndrome
Fever, rigidity, mental status changes, autonomic
instability, myoglobinuria (due to rhabdo)
FEVER
o F- fever
o E- encephalopathy
o V- vitals unstable
o E- enzymes increased
o R- rigidity of muscles
o Types of statistical analyses
Meta-analysis
Groups the results of several trials to increase statistical
power and provide an overall estimate of the effect of
an exposure on an outcome (ex. Multiple trials to giving
 cocoa and monitoring its affects on blood pressure.
Then pool the results to see how cocoa, overall, affects
blood pressure)
If the 95% confidence interval does not cross the
number used in the null hypothesis, the null value,
(usually 0), then the results are statistically significant
Hereditary Spherocytosis
o Lack of spectrin and ankyrin produced RBCs that have fragile
cytoskeletons. The result is hemolytic anemia (spleen lyses irregularly
shapped RBCs), jaundice (RBCs release bilirubin when lysed),
splenomegaly (spleen is swollen because the irregularly shaped RBCs
get stuck trying to pass through the spleen causing it to inflame)
o Pts can appear fine most of the time and, but when under stressful
conditions (like a viral infection), hemolysis is triggered in the spleen
Sickle cell
o The negatively charged glutamate is replaced by nonpolar Valine
at position 6 of the beta globin chain making the mutated Hb more +
charge
When put on gel electrophoresis, the mutated Hb Beta chain is
now more + charged. The blood starts at the negative side and
migrates to the positive side. The mutated Hb, which is more
positively charged, will move slower than normal Hb towards
the positive anode so it wont get as far.
o Conditions that promote sickling.
Low oxygen levels on hemoglobin
Organs with high O2 demands (brain, muscle, placenta)
promote sickling by extracting more O2 from the blood
(oxygen unloading]
High amounts of 2,3,-BPG will cause O2 to be dumped in
the tissues. Since hemoglobin now has less O2, it will
sickle
Low amounts of 2,3-BPG will cause O2 to stay attached
to hemoglobin and not be dumped in to tissues. This
will DECREASE sickling
Increased acidity
Low blood volume (dehydration)
o Parvo B19 Can cause an aplastic crisis
o Crew Cut appearance of skull on xray due to marrow expansion
from increased erythropoiesis
o Autosplenectomy can occur (overworked and infarcted spleen shuts
down)
Will see Howell Jolly Bodies
Increases risk of infection by encapsulated bacteria
o Two Types
HbS
 Negative glutamate replaced by non-polar neutral
valine
Not as bad as HbC
HbC
Negative glutamate replaced by positively charged
Lysine
HbC is more positively charged than normal Hb and
HbS. Will most slowest on gel electrophoresis and reach
the least far.
Schizotypal vs. Schizoid vs. Schizoaffective vs. Schizophrenia
o Schizotypal:
Cluster A personality disorder weird
Socially isolated
Believes in things society believes are false (magic)
May have brief psychosis
Isolated + magic
o Schizoid:
Cluster A personality disorder weird
Introverted and socially withdrawn
Feels no need to form emotional relationships with other
people
Isolated

o Schizophrenia
Lasts greater than or equal to 6 months
SX: must include at least 2 positive SX (hallucinations,
delusions, disorganized behavior, disorganized speech)
o Schizophreniform
Lasts 1-6 months
Same SX as Schizophrenia
o Brief Psychotic disorder
Lasts less than 1 month
Same SX as schizophrenia
o Schizoaffective disorder
Schizophrenia + mood disorder (depression or bipolar)