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 : 66025466602546 Bethesda (MD). Genes and disease. National Library of Medicine (US), NCBI.National Library of Medicine NCBI Axelsson, U.; Laurell, C. B. : Hereditary variants of serum alpha-1-antitrypsin. Am. J. Hum. Genet. 17: 466-472, 1965. PubMed ID : 41585564158556