FAMILY/ The Italian Doctors Are Mutating The Gene In a Dish

All proteins are long chains of amino acids. An amino acid, in general, looks like this:



The "R" in a box represents the variable group. Differences in the R group are how we get the twenty-two standard amino acids we use to make the proteins in our body that are responsible for every thing from muscles to the channels in the membranes of neurons that allow us to think and move.

The NH2 shown on the left is an amine group, and the COOH shown on the right is a carboxylic acid group - this is how the amino acid got its name. When you line the carboxylic acid end (C terminus) of one amino acid up with the amine end (N terminus) of another amino acid, an OH comes off of the carboxylic acid, and an H comes off of the amine. The OH and the H come together to form water, and what's left of the carboxylic acid and the amine come together to form the peptide bond, like this:



Our genes/DNA are what give the protein manufacturing infrastructure in our cells the information for what particular amino acids to string together to make the very specific proteins we need for every biological task we carry out. The string of amino acids, held together by peptide bonds, that make up a particular protein is referred to as its primary structure. More complex interactions between the amino acids allow proteins to have secondary, tertiary, and quaternary structure, as well, so one chain of amino acids can fold itself up into an intricate shape.

Many of the important protein structures in our body are made of several individual proteins interacting. (This interaction is the definition of quaternary structure.) This is the case for the hERG protein, a potassium ion channel that allows the heart to end each heartbeat and get ready for the next at an appropriate rate and rhythm. That process in the heartbeat can be called ventricular repolarization, and on an ECG it is referred to as the QT interval:



The KCNH2 gene is the location on the DNA map that tells the protein manufacturing infrastructure in our cells how to make the largest part of the hERG potassium channel. Different mutations in this gene can cause the QT interval to be either too long, lasting more than 430 milliseconds (Long QT sydrome, specifically LQT2) or too short, lasting less than 300 ms (Short QT syndrome, specifically SQT1). Long QT syndrome is more common than Short QT syndrome. Which one does our Chemical's family have?

SQT1 is caused by replacing the amino acid asparagine in position 588 in the chain with the amino acid lysine. The big difference between these amino acids is that asparagine is neutral, not positively or negatively charged, while lysine is positively charged. The images below don't show where the charge is. I haven't figured that out yet.


asparagine


lysine

The differences in charge and shape between these two amino acids change the way the long chain is able to fold. This one change in primary structure ends up changing the secondary, tertiary, and quaternary levels of structure in the entire hERG potassium channel. Just like everything else in life, a change in structure is also a change in function. For SQT syndrome, this change results in a faster passage of potassium through the channel out of the cardiac cell - a gain of function - that makes the ventricles able to contract before they have enough time to fill with blood.

There seem to be multiple mutations between positions 35 and 36 on chromosome 7 that can cause LQT2. These mutations cause a loss of function in the hERG potassium channel, reducing the rate at which potassium can leave the cell. This makes the ventricles unable to contract when they should because they take too long getting back to their baseline potassium levels.