L2 AATD

Question 1

Where the alpha 1 anti-trypsin is produced ?

Answer 1

Mainly by the liver

Less amounts by :

• macrophages
• monocytes
• lung epithelial cells

Question 2

What is Alpha-1 Antitrypsin Function ?

Answer 2

Its main function is to protect the lung against proteolytic damage from Neutrophil Elastase, which is secreted by neutrophils and macrophages during inflammation to destroys bacteria and host tissue.

Question 3

What is the mechanism of AAT ?

Answer 3

1- AAT catch NE by reactive loop

2- make some changes to the structure ( AAT lose some Beta sheets )

3- flings it to the other side

4- both enzymes will be non-functional anymore.

Question 4

Where does AATD is common ?

Answer 4

In Northern European and Iberian descent. ( starts in Sweden )

Question 5

What is the protective threshold of AAT ?

Answer 5

11 mM ( below this is deficiency )

Question 6

Sometimes we have different patients who have the same disease but with different phenotypes. WHY?

Answer 6

1. Due to environment

2. Due to the type of the genetic defect ( genetics)

Question 7

What are the clinical manifestations of AATD ? When they normally start ?

Answer 7

1. Lung (most affected)
   - COPD with early manifestation of emphysema
2. Liver
   - liver cirrhosis ( with reduced function or failure )
   - hepatocellular carcinoma
3. Skin
   - panniculittis ( hardened skin with painful patches )

These manifestations start at 20-50 years

Question 8

What is AAT gene ? Where it is located ?

Answer 8

1. SERpin Peptidase INhibitor, clade A member 1.
   ( SERPINA1 )
2. Located on the long (q) arm of chromosome 14 at position 32.1. (14q32.1)

Question 9

What is the structure of SERPINA1 ?

Answer 9

Made of 4 coding exons … 3 non coding exons … 6 introns between them

Coding exons :
II/III/IV/V

non-Coding exons:
IA/IB/IC

Question 10

Where you can find the reactive loop in the gene ?

Answer 10

In coding exon V

Question 11

What are the two forms of mutations that can cause AATD?

Answer 11

1. Mutations in the gene can lead to a shortage (deficiency) of alpha-1 antitrypsin
2. Mutations in the gene can lead to an abnormal form of the protein that cannot control neutrophil elastase causing AATD.

Question 12

What is the structure of AAT ?

Answer 12

• Made of 394 a.a. ( active methionine residue is in 358 position )
• 3 beta sheets
• 8 alpha helices

Question 13

What is the importance of meth358 ?

Answer 13

It is the pate that is located in the reactive loop and will attach to NE to destroy it

Question 14

What is AATD mode of inheritance ?

Answer 14

Autosomal co-dominance

In which two alleles of a gene pair in a heterozygote (both have full phenotypic expression.)

Question 15

What are the main allele forms of AATD ?

Answer 15

M —> normal amounts (lower normal values is 20 mM / in 95% of population )
S —

Question 16

What is the difference between ZZ and SS ?

Answer 16

In ZZ the mutation will lead to widening of beta sheets and their polymerization in the reactive of one with beta sheet of other so will be trapped within the liver
So it will cause ( liver and lung ) damage

In SS the mutation making it unstable so it will be degraded so the ( lung ) is damaged

Question 17

In Which combination of genotypes the genetic councilling will be really beneficial?

Answer 17

Any combination that can give zz or sz

Question 18

If a patient has a SZ genotype, does that mean that he will have the disease?

Answer 18

Patient w/ SZ who have level above the protective threshold, they are clinically fine (no problem), but some of the patients have level below the threshold

Question 19

What are the challenges of gene therapy ?

Answer 19

1. Safety.. retroviruses are distributed randomly so it can cause cancer
2. Effectiveness … we can’t use adenoviruses as they are :
   - not integrated in the genome so lost with division
   - high doses can lead to complications