Editing Gene Mutations (section)

== GJB-2 Gene Problems ==

The Gap Junction<ref name="gap-junction" />Protein Beta-2 (GJB-2) gene codes for<ref name="dna-basics"/> the protein Connexin-26. As you can imagine, a protein can break in many ways. One common way is for it to be incomplete because a mutation in the gene that codes for it causes it to be not fully formed.

Here's one of the gene mutations we have in GJB-2: <code>NM_004004.6:c.71G>A p.(Trp24Ter)</code>. Interpreted, this tells us that in the GJB-2 gene, at position 71, a nucleotide G was replaced by a nucleotide A. This transforms the template from TGG (add Tryptophan to the chain) into TGA (a stop codon) at position 24. This silly typo in the code causes the resulting attempt at making Connexin-26 to stop at the 24th amino acid, resulting in this 23-amino-acid long protein that is unlikely to do the job because it's supposed to be 226 amino-acids long.

A single mutation won't destroy hearing<ref name="rna-qc"/>, but two of this will be catastrophic because there's no way to make a functioning Connexin-26. The reason why Connexin-26 is particularly necessary here is in its role in maintaining constancy between the endolymph (the fluid of the inner ear) and the cochlear membranes. The [[wikipedia:Hair cell|wikipedia article for stereocilia]] has a nice animation showing how sound reaches them. The crucial bit here is that when they bend, K+ ions flow into them and the resulting change in voltage sends everything into motion. '''Then the K+ ions flow out''' and everything is back to normal for more detection.

This is where Connexin-26 comes in. It creates the gap junctions<ref name="gap-junction" /> through which the K+ ions move back out. If the Cx26 isn't correctly made, it's not going to work and K+ ions get stuck in there. This means that the cells won't function, and worse, they will eventually die because they've got higher concentrations of potassium than the surrounding liquid and osmosis causes more liquid from the outside to flow in, blowing up the cell.

Once the cells are dead, there's no regenerating them, so the game is up. This is part of why novel gene therapies involving mutations like this need to be stuck into little babies' ears. The cells are full of too much potassium and so on, but they aren't dead yet. If you fix the recycling mechanism, they will live!

But notice that this is a progressive disease: over time things get worse. This means that there is a short window to actually get to the cells and fix them.