Alpha 1 Antitrypsin Deficiency By Kyla Turnquist
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’
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
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).
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
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.
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.
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