Alpha 1 Antitrypsin Deficiency

1
Alpha 1 Antitrypsin Deficiency

• By Kyla Turnquist

2
Overview of Disease

• Alpha-1-antitrypsin deficiency leads to a
  condition known as Chronic Obstructive Pulmonary
  Disease (COPD) or emphysema of the lungs.
• Clinically
• Shortness of breath
• barrel chest

3
Overview of Disease

• Liver Disease
• Alpha 1 Antritrypsin secreted from the liver
• The improperly folded protein cannot be secreted,
  and buildup causes liver damage.
• Clinically
• Cirrhosis may develop in patients with
  alpha-1-antitrypsin deficiency
• Reduced liver function
• Inflammation of liver? severe fibrosis of the
  liver
• Liver failure

4
Genotype

• There are many variants for alpha1 AT Deficiency
• Most common in the United States is the S variant
  (SS) others include MS, MZ, or ZZ
• The Z variant is due to a substitution on the
  distal end of chromosome 14, (Location 14q32.1 )
  worst variant
• Most commonly the substitution is Glutamic acid
  is replaced by lysine at position 342
  (Glu342Lys).

5
Protein Function

• The normal function of the alpha 1 antitrypsin is
  to counteract the effects of neutrophil elastase
• Enzyme in the lung used to destroy bacteria,
  cellular debri
• Without the inhibition of neutrophil elastase,
  the enzyme destroys tissue surrounding alveoli,
  causing trapped air? emphysema.
• A1AT functions in other organs, but main damage
  occurs in lungs

6
Image of A1AT protein
7
Secondary and Tertiary Structure
8
Point Mutation of Glutamic Acid to Lysine at
position 342
9
Changes in Function of Protein

• The variant of glutamic acid to lysine causes a
  slight difference in the folding of the protein
  which inhibits normal function.
• The amino acid interacts with surrounding amino
  acids causing the abnormal fold.

10
Changes in Phenotype

• The abnormal folding inhibits proper function of
  the protein. It therefore cannot escape the
  liver, causing liver disease and cirrhosis due to
  scarring. The non-functioning protein cannot
  protect the lungs against the enzyme nuetrophil
  elastase, and emphysema develops.

11
Works Cited

• Lai, E. C. Kao, F.-T. Law, M. L. Woo, S. L.
  C. Assignment of the alpha-1-antitrypsin gene
  and a sequence-related gene to human chromosome
  14 by molecular hybridization. Am. J. Hum. Genet.
  35 385-392, 1983. PubMed ID 6602546
• Bethesda (MD). Genes and disease. National
  Library of Medicine (US), NCBI.
• Axelsson, U. Laurell, C. B. Hereditary
  variants of serum alpha-1-antitrypsin. Am. J.
  Hum. Genet. 17 466-472, 1965. PubMed ID
  4158556