Myopathies

Question 1

What is Classical Laminin composed of?

Answer 1

α1 and α2 chains; β1 and β2 chains; and a γ1 chain.

Question 2

What is Long Laminin composed of?

Answer 2

A α5 chain; β1 and β2 chains; and a γ1 chain.

Question 3

Which Laminin type can self assemble?

Answer 3

Long Laminin.

Question 4

What is the function of laminin?

Answer 4

Structural components of basement membrane

Attatchment sites for cell surface receptors (e.g. dytroglycan and integrins)

Question 5

What Laminins are in Adult skeletal muscle?

Answer 5

Two lamin isoforms

Containing β1 or β2, γ1 and α2 chain

Question 6

What chain is common in all lamin?

Answer 6

α2 chain

Question 7

What is lamin in skeletal muscle development composed of?

Answer 7

In addition of adult lamin chain α4 and α5 chains

Question 8

What is the main causes Congenital Muscular Dystrophy?

Answer 8

Mutations of the laminin α2 chain

• Deficiency of laminin α2 chain (50% of CMD) Absence of lamin α2 chain, lamin α4 and α5 chains upregulated
• Partial deficiency - in frame deletions in N-terminal, may retain some function - milder forms of CMD

Question 9

How deficiencies in the α2 chain affect Laminin functioning?

Answer 9

The laminin will no longer be able to bind α-dystroglycan.

• deficiency topless protein C-terminus won’t interact - cell membrane ruptures
• partial, can interact with transmembrane proteins but receptor/ligand interaction affected

Question 10

What is the dystrophin-glycoprotein complex (DGC)?

Answer 10

It is a multi-protein complex composed of dystroglycan, α, β, γ and δ sarcoglycan and sarcospan. located in plasmamembrane (sarcolemma)

Question 11

What does the dystrophin-glycoprotein complex (DGC) bind to?

Answer 11

• laminin on the outside of the muscle cell

- dystrophin on the inside of the cell.

Question 12

What mediates the interaction of the dystrophin-glycoprotein complex (DGC) to its ligands?

Answer 12

β-Dystroglycan.

Question 13

What is Dystroglycan?

Answer 13

-One gene, post-translationally cleaved into;
extracellular located α-dystroglycan
And
transmembrane located β-Dystroglycan

Question 14

Describe the structure of α-Dystroglycan.

Answer 14

Dumbelled shape
Rod-like domains -heavily glycosylated
Sugar chains mediate binding to laminin

Question 15

In some forms of Congenital muscular dystrophy, the α-dystroglycan is modified. What is the modification and what is the consequent effect?

Answer 15

It is hypoglycosylated, which makes it unable to bind to laminin.(connection between matrix and cytoskeleton lost)

Question 16

What are integrins?

Answer 16

Heterodimeric protein - binds to ligand outside cell
composed of α and β chains
Cytoplasmic domains connected via adaptor proteins to cytoskeleton

Question 17

What integrin type is mainly expressed in skeletal and cardiac muscle?

Answer 17

Integrin α7β1

Question 18

Describe integrin α7β1 deficiency.

Answer 18

Mice
-progressive muscular dystrophy
-affects myotendinous junctions
Human
-out of reading frame mutation
-mild form of CMD

Question 19

What is dystrophin?

Answer 19

• Huge gene
• component of DGC
• Binds N-terminus to actin cytoskeleton, C-terminus toβ-dytroglycan
• x-chromosome

Question 20

What causes Becker Muscular Dystrophy and Duchenne Muscular Dystrophy?

Answer 20

Dystrophin deficiency