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Posted by on Jun 21, 2013 in Q & A |

What Is The c-KIT Mutation?

Still having trouble with the c-KIT mutation?? You're not the only one! Please head for the Masto Townhall forum to find the answers.

Whoa, Tiger, Steady On …

If you are unfamiliar with genetics, this may be a bit difficult to grasp out-of-context. Maybe you'd want to review the genetics stuff in the post How Can I Learn Genetics? first.

But if you are in a hurry, just watch this video as a necessary prerequisite to what follows; pay particular attention to the sentence at 01:43 to 01:46  and the explanation about when someone says you have your father's hair  at 02:01 to 02:17


Do I Look Fat In These Genes?

The important bits in the above clip are the following:

  • The complete set of instructions to make your body work is located in the nucleus of every single cell.
  • Every cell has one copy of the same set of instruction, called DNA.
  • DNA is long molecule, formed like a ladder.
    • The vertical rails (or styles if you're in the UK)  are composed of two long strands of sugar and phosphate.
    • Each of the horizontal rungs is made of two pieces,  linked in the middle. Those two pieces are called bases.
  • There are four types of bases, each type is represented by the letter A or T or C or  G
  • Every rung between the rails can be formed of any 2 types of bases, for example AT or CG or TA or GC
  • There's about 98% of the DNA we don't know what it is  for, and (at the time of writing) is believed to be junk.
  • There's 2% of the DNA which actually contains the necessary instructions, by way of the letter-coded rungs.
  • The contents of these 2% of the DNA are called the genes.
  • We have about 20,000 genes in our body
  • While ALL the genes are present in ALL the cells, only certain genes are switched ON for a specific cell type. So,
    • a blood cell will have a specific set of genes ON,
    • a skin cell will have a different set of genes ON,
    • a brain cell will have yet another set of genes ON… You get the picture
  • Genes tell a cell how to function, they tell the cell how to manufacture individual cell pieces called proteins
  • Now, go to a cell's DNA, pick one of the genes which is ON and climb that gene's DNA ladder while calling the letters on each of the rungs.
  • The sequence of letters you'll be calling is the recipe that tells the cell how to make a specific protein.

I’m Confused …

Well, OK. Just forget everything we've said, except:

  • Genes tell a cell how to function
  • A gene contains the instructions to manufacture a protein
  • The way that the gene tells the cell how to manufacture a protein is by reading the letters on the rungs of the gene's DNA ladder
  • The sequence of the letters is all important, much in the same way that the sequence of letters are important to write words. If the letters get jumbled, the words can change meaning or be meaningless altogether.

Meet Billy The Kid

Now, who's is that kid we're all talking about? Is it a juvenile delinquent?

No. The kid in question is actually called c-KIT. And it is actually the name of a gene. The c-KIT gene.

But wait, there's more!

Remember that genes are instructions to create proteins. So, once we've run the c-KIT gene instructions, we manufacture a cell product. That product is called the c-KIT protein.

The Devil Has Many Names

The c-KIT protein is variously called by different names, like

  • Mast/stem cell growth factor receptor
  • SCFR
  • proto-oncogene c-Kit
  • tyrosine-protein kinase Kit
  • CD117
  • c-KIT receptor

Go figure! Why make it easy when you can make it complicated?

Have We Met Before?

You may remember we've already talked about the c-KIT receptor in the earlier post What Are Receptors? So, now you know that that c-KIT receptor we talked about in the earlier post, that same receptor, which we learned back then, sits on the cell membrane, is actually a protein. And that protein actually originated from running the c-KIT gene instructions through the cell's protein manufacturing  machinery.

Remember :

c-KIT gene in nucleus contains c-KIT protein manufacturing instructions. These instructions are executed in the cell manufacturing plant. The running of these instructions produces the c-KIT protein inside the cellThe c-KIT protein is then pushed up through the cell membrane and becomes the c-KIT receptor on cell membrane. Notice we're always talking about the c-KIT ‘something', either the c-KIT gene, c-KIT protein, c-KIT receptor.

So, the c-KIT protein which was manufactured inside the cell suddenly pops-up outside the cell and implants itself on the cell surface, ready to listen to external signals.

At this stage it is strongly advised to re-read the post about receptors and come back here for more.

Ninja Mutant Turtle

Welcome back!

Let's now talk about mutations and remind ourselves what a mutation is by watching a video snippet. And please do pay attention at 00:05 to 00:14 in the video.


Did you pay attention? If not, here's the important bit.

  • A mutation is a damage to a gene.
  • There are several types of mutations.
  • The type we're interested in is the ‘point mutation'. That's the type of mutation that affects the c-KIT gene and causes out mast cells to proliferate.

As you've heard in the video:

In a point mutation, one base pair is replaced by another. Now that the coding has changed, the gene may not work properly.

So, in a point mutation, one rung of the ladder is replaced by another. Therefore, the sequence of the letters of the rungs in the gene are scrambled. Since that letter sequence is the instructions for the cell to manufacture the c-KIT receptor protein, and that sequence is now wrong because of the mutation, the c-KIT receptor protein is incorrectly assembled.

Who Left The Lights On?

Wait! Say What?

Just one change in the letters causes me all that misery?

True story! Just one letter change has dramatic consequences. You see, the c-KIT receptor is the guy that causes mast cells to proliferate in an uncontrolled fashion.

The c-KIT receptor is the ‘antenna' which receives the signal which tells the mast cell that it must reproduce itself. When the c-KIT ‘antenna' receives that signal (a signal which is called the Stem Cell Factor), the c-KIT flicks the ON switch for some machinery inside the cell which causes the cell to split and ‘give birth' to one more incarnation of itself.

The letter change in the gene, the mutation we were talking about?  That  has the consequence  that the ON/OF switch is incorrectly manufactured. That manufacturing defect causes the cell reproduction switch to be permanently ON, leaving the mast cell production machinery to manufacture mast cells all the time.

That means that the mast cell reproduces itself, even though no Stem Cell Factor signal was received to do so. That causes abnormal mast cell proliferation, which is the hallmark of mastocytosis.

In medical articles, you will read the term “heterozygous activating mutation of KIT”, which is what the letter change is called. You will also read about the “constitutive activation”.  That's the name given to the ON/OFF switch defect.

Location, Location, Location

I am sure you've scratched your head when you read about the “D816V mutation”. Well, it's the same thing as the mutation we were talking about, but with a bit more precision.

The following is not strictly correct, but I have taken editorial license to simplify the concept so that you can understand it. Pretend that the number 816 refers to the location of the ladder rung which has been mutated, and you won't be far off from the truth. So, the mutation happened on the 816th rung of the ladder. As to the D and V, pretend that these are the letters that have been changed. So, the D has been changed to a V.

so, let's pretend that D816V means that a mutation has caused rung 816 of the c-KIT gene ladder to change from a D-type rung to a V-type rung.

A typical medical article will read something like this:

The D816V heterozygous activating mutation of KIT results in a single base pair substitution of A in wild-type to T in mutant at nucleotide position 2447. This substitution changes theamino acid at codon 816 from aspartic acid (D) to valine (V), leading to constitutive activation of the tyrosine kinase II domain (TK2), resulting in cell proliferation and inhibition of apoptosis.

I hope you now understand the c-KIT mutation a bit better. If not, remember:

Head for the Masto Townhall forum and ask questions!