genetics

Question 1

Familial adenomatous polyposis is associated with a mutation in the APC gene. What the role of this gene in normal cellular function and what changes when its KO.

Answer 1

APC normally phosphorylates beta catenin so it’s degraded by a cellular proteasome and levels are kept low; in the absence of WNT.

When WNT binds the cell, APC binding of beta catenin doesn’t result in phosphorylation, thus beta catenin can act as a transcription factor for cellular growth by removing the groucho molecule from off the nuclear DNA .

Question 2

APC when mutated, is involved in which of the following

1 tumor initiation
2 tumor progression
3 tumor reactivation
4 tumor suppression

Answer 2

1 tumor initiation, via inhibited inhibition of beta catenin

Question 3

KRAS is normally involved in signal transduction via what mechanism? What type of gene is it derived from?

Answer 3

GTPase converting GTP into GDP

Proto oncogene chrom 12

Question 4

APC is ….

1 AD and progresses when 2nd APC is lost
2 AR and progresses when 2nd APC is lost
3 AD and activates cell growth alone
4 AR and activates cell growth alone

Answer 4

1 AD and progresses when 2nd APC is lost

Question 5

Which molecular mechanisms are associated with hereditary non-polyposis colorectal cancer? What’s another name for HNPCC?

Answer 5

Mismatch repair/misincorporation and replication slippage/microsatellites

Lynch syndrome

Question 6

Which mismatch repair mutation is associated with delayed onset, decreased penetrance? How common are they?

Answer 6

nMSH 6 delayed onset
hPMS2 decreased penetrance
both uncommon

Common are hMSH 2, hMLH1

Question 7

Which gene mutation most commonly leads to gene slippage due to faulty repair by the MMR enzymes? What is the normal and abnormal function of the gene like?

Answer 7

TGF-beta R2 gene

normal- inhibits cell proliferation, immune reg,

Excess or deficient expression- will promote angiogenesis, ECM production and inhibit immune surveillance.

Question 8

The most common mutation leading to TGF-beta R2 changes occurs in what region of the gene? What is the result of this mutation?

Answer 8

BATII region which contains 10 Adenine bases in a row. This is the most common site of mutation for colorectal cancer and almost always creates a stop codon and a non functional protein, so there is no dimerization of signaling.

This leads to angiogenesis , cell proliferation and invasion.

Question 9

Chromosomal instability is more common in adenomas or carcinomas? Which will likely display dipolid and which aneuploidy?

Answer 9

Carcinomas will have more unstable chromosomes with large deletions and display aueploidy.

Question 10

large chromosomal instability is associated with what of outcomes?

Answer 10

low relapse and overall survival

Question 11

Gilbert syndrome is the result of a disease process involving more than just UGT1A1 explain

Answer 11

Gilbert syndrome is the result of both a mutation of the UGT1A1 gene and low grade hemolysis due to G6PDD. This is a type of synergistic heterozygosity, where heterozygosity across different loci contribute to disease.

Question 12

Synergistic heterozygosity is the result of UGT1A1 and various genetic defects such as:

Answer 12

Excess heme in blood-hyperbilirubenemia infants
G6PDD
Spherocytosis
ABO hemolytic disease

Decrease in bilirubin uptake in the liver-hyperbilirubenemia infants
OATP-2

Question 13

How are Heinz bodies formed?

Answer 13

From precipitated hemoglobin in ROS damaged RBC; from G6PDD leading to an decrease in glutathione a important antioxidant.

G6PDD x-linked recessive

Question 14

What are two ways you can detect a G6PDD in neonates?

Answer 14

acute hemolytic even triggered by infection or naphtalene exposure which causes a rapid rise in total serum bilirubin.

Gilbert syndrome-low grade hemolysis coupled with UGT1A1 mutation.

Question 15

Why are only RBC affected by an AR Pyruvate Kinase deficiency?

Answer 15

B/c the mutation of the PKLR gene only codes for the PK in RBC.

Question 16

What’s the theory of how Pyruvate kinase deficiency leads to anemia?

Answer 16

Decrease in glycolysis, decrease in ATP, Decrease in ATPase, influx of Na+, cell swelling and hemolysis, spleen filters rupture RBC, anemia. Ironically this increases 2,3 BPG and shifts Oxygen dissociation curve to the right making the release of O2 to tissues easier and compensates for the anemia.

Question 17

Your infant patient has a persistant jaundice, a negative Direct antibody test and microscopy of their RBC indicates no sphedrocytosis or elliptocytosis. What’s a possible genetic cause?

Answer 17

Pyruvate kinase deficiency.

Question 18

Your attending is pimping you on questions and says that your infant patient has two different disease causing alleles a the same locus which is the cause of their disease state. What is this called?

Answer 18

compound heterozygosity