Lecture 20 - Cytoskeletal Protein Defects

Question 1

What is hemolytic anemia?

Answer 1

• anemia resultant of shortened lifespan of red blood cells

- typical lifespan is 120 days

Question 2

What is hereditary spherocytosis?

Answer 2

• hemolytic anemia resultant of mutations of erythrocyte membrane skeleton protiens (primarily spectrin/ankryin)
• results in spherical and fragile RBCs

Clinical presentation:

• hemolysis
• anemia
• splenomegaly

-common in people of Northern European descent (1/2000)

Question 3

What is the osmotic fragility test? What does it indicate and why?

Answer 3

• place a few drops of blood in hypotonic saline
• fragile RBCs will lyse
• after spinning down, those with fragile RBCs will have a red solution due to leaked hemoglobin and normal will have a pellet

-this indicates hereditary spherocytosis

Question 4

What are the different proteins involved in the erythrocyte membrane skeleton?

Answer 4

• spectin (α and β)
• ankyrin
• band 3
• band 4.1a
• band 4.1b
• band 4.2

Question 5

What is the Nan mutation?

Answer 5

• mutation of Klf1 which is a DNA binding protein which targets erythrocyte membrane skeleton genes
• likely a cause of hereditary spherocytosis
• results in change of Arg-Asp-Arg (RDR) instead of highly conserved Arg-Glu-Arg (RER)

Question 6

What is Duchenne muscular dystrophy?

Answer 6

• complete absence of cytoskeletal protein dystrophin
• X-linked recessive
• most common fatal neuromuscular genetic disease
• eventual loss of lung and cardiac function

Question 7

What is the function of the dystrophin protein?

Answer 7

-provide structural stability to muscle cell membrane during contraction and relaxation

Question 8

What are the clinical signs of Duchenne muscular dystrophy?

Answer 8

Clinical presentation:

• elevated CK
• slow walking/weakness
• progressive muscle cell degeneration
• pseudohypertrophy of muscles (fat and fibrous tissue replacement)
• lordosis and kyphosis
• frequent falls

Question 9

What is the Gower maneuver and what does it indicate?

Answer 9

• child gets on hands and knees then walks hands up legs to raise upper body
• can indicate Duchenne muscular dystrophy

Question 10

What is Becker muscular dystrophy?

Answer 10

• result from pressence of mutated dystrophin gene
• similar but more mild than DMD
• X-linked recessive
• is not always familial

Question 11

List possible treatments for DMD and what complications are present if any.

Answer 11

• growth factor (creates more bad muscle)
• gene therapy (gene is too large for viral introduction
• microdystrophins (immunogenicity)
• exon skipping (immunogenicity)
• stop codon skipping (immunogenicity)
• use of retinal dystrophin (works?)