As many in the cystic fibrosis community are aware, the new, breakthrough CF medication Orkambi is only approved for those patients who have two copies of the cystic fibrosis gene mutation Delta F508 (Double DF508). But what really is this particular gene mutation? That is the topic of today’s posting.
There are over 1,500 mutations that have been identified on the gene CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). According to the website Medscape.com, only approximately 20 mutations of those 1,500 mutations occur commonly in the Caucasian population (http://www.medscape.com/viewarticle/576200_2). DF508 is just one of those mutations, and is caused by a deletion of the three nucleotides that comprise the codon for phenylalanine (f) at position 508.
DF508 is the most frequently identified CF gene mutation throughout the world. As a point of reference, an estimate of those with CF who carry DF508 on a worldwide basis is said to be at 75% (http://www.who.int/genomics/publications/en/HGN_WB_04.02_report.pdf).
DF508 is a mutant CFTR protein which cannot be folded into its proper shape when produced. The quality control mechanisms within the cell destroy this abnormal protein before it can reach the cell surface where its major normal function is to act as a channel through which chloride ions can pass in and out of the cell (http://www.cfmedicine.com/htmldocs/cftext/genetics.htm). On the other hand, a correctly formed CFTR protein opens channels in the cell membranes that releases chloride ions out of cells, which causes osmosis to draw water out of the cells (https://en.wikipedia.org/wiki/%CE%94F508).
In fact, part of the way that Orkambi works successfully is by one of its combinations assisting to move the defective CFTR protein to its proper place at the cell surface. As well, another combination of Orkambi increases the activity of that protein once it is there, supporting the flow of salt and fluids, which helps thin the thick mucus that builds up in the lungs and other organs (https://www.cff.org/Living-with-CF/Treatments-and-Therapies/CFTR-Modulators/CFTR-Modulator-Basics/).
Scientists have estimated that the DF508 mutation occurred over 52,000 years ago in Northern Europe. A hypothesis that supports the evolvement of this mutation is that it causes a positive effect by reducing water loss, since DF508 inherently does not allow the release of water from the cells, during cholera, which was a common cause of death in Europe when the mutation first appeared (https://en.wikipedia.org/wiki/%CE%94F508).
Please check out the introduction of this posting at Youtube at https://youtu.be/TihjjAhMf2Q
NEXT POST to Our CF Matters Hawaii, September 26th – “Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). What is it?”