Alport Syndrome - Checked and Complete

Question 1

What are the two layers of the basement membrane?

Answer 1

Lamina Lucida

Lamina Densa

Question 2

In which layer is collagen IV an integral part?

Answer 2

Lamina densa (this is partially why it is dense)

Question 3

Describe Type IV collagen

Answer 3

Forms networks

Six isoforms each from different gene, found on 3 different chromosomes (13, 2, and X)

Collage IV triple super helix formed by combination of any of these isoforms

Question 4

List some common triple helix collagen IV isoform combinations and where they are found

Answer 4

** α1-α1-α2** in all BMs

α3-α4-α5 in the BMs of glomerulus, ear, eye, and lung

α5-α5-α6 in skin and smooth muscle cell BMs.

Question 5

Describe how Collagen IV aggregates

Answer 5

N-terminal domain associates with 4 molecules in an anti-parallel fashion to form an overlapped spider-like 7S domain

7S domains interact via globular carboxyl terminal NC1 domains

“CHICKEN-WIRE”

Question 6

What are symptoms of Alport disease?

Answer 6

Hematuric Nephropathy

Proteinuria

Renal Failure

Hearing Loss

Question 7

What are 3 common mutations leading to Alport Syndrome?

Answer 7

COL4A3

COL4A4

COL4A5

(Mutations of collagen IV isoform 3-5)

Question 8

What chromosome carries mutations of COL4A3-4? COL4A5?

Answer 8

isoforms 3-4 found on chromosome 2

isoform 5 found on chromosome X

Question 9

What is the most common Alport syndrome mutation?

Answer 9

Isoform 5 mutation

Question 10

What happens to males with the isoform 5 mutation? females?

Answer 10

Males get fullblown Alport Syndrome

Females get hematuria but no kidney failure

Question 11

How is the isoform 5 mutation inherited? Isoform 3 &4?

Answer 11

Isoform 5 inherited X-linked recessive

Isoform 3-4 autosomal recessive

Question 12

When it comes to collagen, why might a mutation on the Carboxy terminus be more dangerous?

Answer 12

C-terminus is where single strands bind and wrap together to form triple helix

Question 13

How might you diagnose Alport Syndrome?

Answer 13

Skin sample for isofrom 5 mutation

Also kidney biopsy to check for isoform 3-4 if isoform 5 mutation not found

If nothing found you can still perform gene sequencing

Question 14

What type of collagen 4 isoform combination is found in the embryonic GBM?

Answer 14

** α1-α1-α2 **

(Changes to 3-4-5 after birth)

Question 15

What is treatment for Alport Syndrome?

Answer 15

Kidney Transplant

ACE inhibitors or Angiotensin-receptor blockers to reduce proteinuria by decreasing intraglomerular pressure

Replacement therapy: EPO for anemia, phosphate binders and vitamin D to manage osteodystrphy, alkali to correct acidosis, antihypertensive therapy for blood pressure