Difference between revisions of "Team:ASIJ Tokyo/Description"

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Alpha-1 Antitrypsin | NIH 3D Print Exchange. (n.d.). Retrieved October 18, 2018, from https://3dprint.nih.gov/discover/3dpx-004450
 
Alpha-1 Antitrypsin | NIH 3D Print Exchange. (n.d.). Retrieved October 18, 2018, from https://3dprint.nih.gov/discover/3dpx-004450
  

Revision as of 23:56, 17 October 2018

PROJECT DESCRIPTION


Alpha-1-Antitrypsin Deficiency: What is it?

A1AT deficiency is an enzymatic liver disorder that results from a genetic mutation in the SERPINA1 gene.

    The SERPINA1 gene codes for the production of the protease Alpha-1 Antitrypsin in hepatocytes. A1AT is a protease inhibitor whose function is mainly to protect delicate lung tissue from damage from other enzymes active in the area. Once produced in the liver, A1AT is secreted from the cells and makes its way to the lungs via the bloodstream.

   The normal version of SERPINA1 is known as the M allele and the mutation that most often results in severe A1AT deficiency creates the Z variant of SERPINA1. The SERPINA1 gene is codominant, so those with two copies of the Z allele are affected most strongly. This is the version of the gene we aimed to correct. As you can see, the mutation is only of a single base pair, and results in glutamine replacing lysine. The relative ease by which we could use CRISPR Cas9 to fix the mutation causing this disease was also a factor in selecting this disease for study.

Mutation Anti-trypsin trying to leave the cell
The E342K mutation in SERPINA1 that causes A1AT Deficiency Secretion of A1AT in cellsl

    The Z mutant version of A1AT is prone to polymerization, rendering the protein unable to be secreted from the cell producing it. This causes the protein to build up within the liver. However, if not polymerized and successfully secreted, the Z type A1AT is fully functional. As a result, those with the ZZ genotype usually only have 10% of normal serum levels. As only a small fraction of needed levels of A1AT are available, the medical complications related to the disease ensue. This can include liver cirrhosis and chronic obstructive pulmonary disease, especially in the form of lung emphysema. These are all because A1AT cannot get to the lungs to protect the tissue and instead builds up in liver cells, causing damage. This in turn, results in recurring respiratory infections, fatigue, unintentional weight loss, and rapid heart beat upon standing. Additionally the deficiency increases one's risk of a rare type of liver cancer.

    The exact prevalence of the ZZ genotype and associated disease is not known, but it is thought to be around 0.1% of the world population, though it varies by ethnic group. Northern Europeans, in particular, have particularly high instances of the mutation, while it is rare in Asian and African populations. The A1AT deficiency is the most common genetic cause of liver disease and the most common reason for liver transplant in children. Additionally, A1AT deficiency often goes undiagnosed or misdiagnosed as asthma. Treatment options are also not convenient or cost-effective - many patients require weekly intravenous augmentation therapy, which can cost up to 100,000 dollars a year - an astronomical amount over a lifetime. These were also factors we considered when selecting this disease.

Sources