White Cool Lecture Oct 3

Question 1

Where are the RBC’s destroyed?

Answer 1

reticulo-endothelial system (liver and spleen)

Question 2

What is hereditary spherocytosis in regards to the RBC’s?

Answer 2

The RBCs are spherical and fragile resulting in increased hemolysis

Question 3

What are the clinical signs of HS?

Answer 3

hemolysis, anemia, and splenomegaly

Question 4

Why is the cytoskeleton important in the RBC’s?

Answer 4

structure
flexibility while moving through the capillaries
strength

Question 5

What is the structure and function of spectrin?

Answer 5

Spectrin provides the RBC with a resilient structure

alpha beta heterodimer with a head to head alignment

Question 6

Describe the steps of the osmotic fragility test

Answer 6

1. place the blood in a hypotonic solution (vary concentration of the solution)
2. water will rush into the cell
3. normal cells will swell and not break
4. the HS cells will swell and lyse

Question 7

Describe what the NAN mouse experiment aimed to test?

Answer 7

To see if there was another cytoskeleton molecule or other unassociated molecule that could be associated with the causation of HS

Question 8

What was the finding in the NAN study in relation to the Fe and the Zn

Answer 8

Instead of having an Fe bound to the cell, the RBC had high levels of Zinc

Question 9

What was the DNA binding protein that was found to have a mutation in the NAN experiment?

Answer 9

Kruppel Like factor 1 (KLF1)

Question 10

Describe the actions of the KLF1

Answer 10

It binds to several promotor regions of ECM molecules

Question 11

What is the binding motif that is highly conserved in DNA

Answer 11

RER

Question 12

What are the various treatments for HS?

Answer 12

blood transfusions
splenectomy
increase the RBCs and Hb

Question 13

Which muscular dystrophy is the most common fatal MD?

Answer 13

DMD

Question 14

What are the treatments that can be provided for someone who has DMD?

Answer 14

glucocorticoids (prednisone)

and supportive measures

Question 15

Describe the genetics of the DMD? What kind of inheritance pattern does it follow? What are the mutations that are involved?

Answer 15

X-linked recessive

frameshift mutation

Question 16

What are the clinical factors of DMD?

Answer 16

dystrophic myopathy 
elevated CK levels that are 50-100 times more than normal 
slow walking and generalized weakness 
waddling 
problems with stairs 
tiptoe walking 
lordosis 
kyphosis 
scoliosis 
necrosis of the muscle fibers (increased tone) 
wheelchair by 13

Question 17

What is the Gower man sign?

Answer 17

When a kid is on the floor and uses his hands to walk up his legs while standing

Question 18

What is the average age for diagnosis of DMD?

Answer 18

4 years and 10 months

Question 19

Define BMD

Answer 19

Becker Muscular Dystrophy

milder from of DMD

Question 20

What are the cardiac issues that are commonly seen in BMD

Answer 20

increased workload on the left ventricle and the enlargement of the left ventricle
heart failure and death

Question 21

Describe the genetics of BMD including the “odd” finding in regards to the genetics, mode of inheritance, and the type of mutations that are typical

Answer 21

• 1/3 of the cases are de novo, meaning that it was not directly inherited in the family
• X linked recessive
• inframe deletions

Question 22

Describe why it was thought that growth factors would be a good treatment for DMD.

Answer 22

myostatin is a cell growth inhibitor, so it was thought that if you treated a pt with DMD with a myostatin inhibitor, it would promote muscle growth

Question 23

What are the cons in using growth factor as a treatment for a pt with DMD?

Answer 23

It makes more defective muscle and is not useful

Question 24

What are the two ways in which gene therapy can be used for someone with DMD?

Answer 24

1. replace the dystrophin gene

2. use microdystrophins

Question 25

What is a microdystrophin?

Answer 25

A smaller yet semi functional form of dystrophin that could be used to generate new forms of dystrophin in pts

Question 26

What are the cons of using the microdystrophins?

Answer 26

immunogenicity

Question 27

What are the cons of trying to replace the dystrophin gene?

Answer 27

It is not able to fit and it is not successful

Question 28

Describe exon skipping ?? edit me

Answer 28

attempting to skip the exons that have the frameshift mutation??

Question 29

Describe stop codon skipping

Answer 29

skipping the premature codon

Question 30

Describe retinal dystrophinin relation to DMD and how it can be used as a treatment

Answer 30

A protein called Dp260 is made in the retina and is present in 30% of people with DMD
If you can utilize this dystrophin making protein in the muscle cells then you can kind of reverse the effects of the DMD

Question 31

What are the pros of using the retinal dystrophin as a treatment for DMD

Answer 31

It avoids immunogenicity because it is endogenous

Question 32

Where is dystrophin found?

Answer 32

inner surface of the membrane

Question 33

What are the 4 domains of the dystrophin

Answer 33

1. N-terminus
2. long spectrin like repeat domain
3. and 4. Cysteine rich and C-terminus domains

Question 34

What is the function of the N-terminus on the dystrophin?

Answer 34

actin binding

Question 35

What is the function of the long spectrin like repeat domain?

Answer 35

it serves as the cytoskeleton domain of the dystrophin

Question 36

What is the function of the cysteine rich and the C domains?

Answer 36

it binds syntrophin (linkers); and binds to the dystrophin associated glycoprotein complex