Cystic Fibrosis Model
Cystic fibrosis is a disease caused when a mutated gene produces a defective protein. A healthy gene produces a working protein with 1 480 amino acids. The damaged gene produces a nonfunctioning protein with
1 479 amino acids. The defective protein is missing the amino acid phenylalanine, which causes this often fatal disease.
Without this amino acid, which make the proteins defective, the cells can not maintain a healthy amount of salt in the cells and bodily fluids. Excess salt in the cells cause water to flow into the cells, to regulate fluids inside the cells which makes the mucus, outside the cells thick and sticky. A condition conducive for unhealthy bacterial growth that results in fatal diseases.
A healthy protein is tube shaped and attaches to the cells outer surface where it will act like a valve that regulates a flow of chloride required for an optimum consistency of cell fluids and to provide free flowing mucus that can wash, clean, and protect the cell surfaces.The most serious effects of this damaged gene is to the lungs, pancreas, and sweat glands.
In the lungs thick mucus clogs the cilia and builds congestion causing a place for bacteria to grow. Similarly in the pancreas a build up blocks the release of enzymes for food digestion and absorption causing malnutrition. The lack of flow in the sweat glands causes a build up of salt know as salty sweat.
It would seem a fix for one defective gene that fails to produce a healthy protein and instead produces one, missing one amino acid, ought to have a simple fix to remedy a simple omission. However that isn’t the case. Research has found upward of 1 900 mutations that creates a malfunctioning Cystic Fibrosis Transmembrane Regulator (CFTR) protein, each requiring its own fix. Of those, 50% have two copies of genes with a Delta F508 mutation, 40% carry one copy of the Delta F508 mutation with a second alternative problem gene, and 10% have a rare mutation that doesn’t include a Delta F508 mutation.
The Delta F508 produces a Cystic Fibrosis Transmembrane Regulator (CFTR) protein that is crumpled so it will not reach the surface of the cell where it is supposed to be. However, if it could move to the surface an additional problem would be its inability to allow chloride ions to pass through it. Which is exactly what happens with one of the rare mutations G551D. This protein can move to the surface of the cell, but it will not allow chloride ions to flow.
For more information on Cystic Fibrosis and a cure see the article in Discover September 2013: Doorway to a Cure: A nonprofit is taking a financial gamble on eradicating cystic fibrosis. by.
|Type of mutation||protein synthesis||maturation processing||Ion channel gating||ion channel conductance||reduced protein|
|Percentage of patients||22%||88%||6%||6%||5%|
|Where in the cell the defect occurs||ribosome||golgi/ER||plasma membrane||CFTR||Plasma membrane, spliceosome|
Source Making Precision Medicine Personal for Cyctic Fibrosis. July 19, 2019 Science