Different mutations and their effects

In my last post I looked at a common mutation that causes deafness: the c.35DelG mutation. This type of mutation, where one of the DNA letters just goes missing, is called a 'frameshift deletion' mutation. Another one, 235DelC, is quite common among Asians and has pretty much the same effect.

Let's pretend that, instead of being a majestic molecule that encodes the very essence of life itself, DNA is a drab children's book. It still is only read as 3 letter words (remember codons). And it has the following line:

Pat and Ann ate ham and ran off

A frameshift mutation might delete a letter and give the following:

Pat and Ann ate ama ndr ano ffa

The sentence is now meaningless, just like the protein that such a mutation creates. But instead of deleting a letter, you could swap it with a different one:

Pat and Ann ate Pam and ran off

You know have a sentence with very different, and sinister, meaning. What are we subjecting our poor kids to? It's function has changed, and this is what happens with DNA - these mutations create proteins that do something, just not what they are meant to do.

Swapping one letter of DNA for another is called a missense mutation. When this happens with Connexin 26, you can get other problems as well as deafness. This is called Syndromic hearing loss.

The picture below shows the Connexin 26 molecule. Each of the coloured circles with a letter represents an amino acid. Scientists have noticed mutations that change a lot of different parts of the molecule. The ones that change the blue circles just cause deafness. But at the yellow parts, the mutations cause other problems too - mostly skin disorders, because that's where Cx26 is most active. And these tend to be missense mutations.

The skin problems can be severe, and can sometimes lead to loss of blood flow to fingers and toes, causing them to drop off, or to blindness.

But if these Cx26 mutations have such a big effect on skin, why does not having Cx26 leave your skin perfectly fine?

Scientists aren't sure, but they suspect it is because of 'gain of function'. The missense mutations mean that the Connexin 26 does things it isn't supposed to do. In this case it is likely it is letting more chemicals pass between cells, which might cause to much skin to grow (hyperkeratosis).

If there are no working Cx26, the skin doesn't seem to have any problems. They reckon this is because there are other Connexin proteins (like Cx30 or Cx43) that do more or less the same thing - you have redundancy there that isn't in the ear for some reason. It is possible that the missense Cx26 molecules also interfere with these other guys and stop them working properly. In genetics this is called Trans-dominance, where a mutated protein prevents healthy proteins from doing their job.

I wrote before about how Connexin molecules bunch together in groups of 6 to form the channels that connect cells. These aren't always the same Connexin molecules - Cx26 might combine with Cx30 or Cx43. These would give different channels, that let different molecules pass through. It might be that a mutated Cx26 is too eager to join up with these other Cx molecules. All the Cx43 and Cx30 proteins join up with the broken Cx26, instead of making their own channels that the skin needs.

So in this case, having a slightly-changed version of Cx26 can be worse than having none at all.

Most of this comes from a paper by Jack Lee & Thomas White, you can read it here if you fancy.
And if you want to know more about different mutation types here is a good guide.

More on mutations

So I know both of my son's GJB2 genes have mutations. What does this mean on a molecular level? Do his cells not make Connexin 26 at all? Or do they all come out wonky?

It seems that this depends on the mutation. And surprisingly enough, having wonky Cx 26 proteins might cause more problems than having none at all.

Genetics is a field of science which still holds a lot of mysteries, despite the fact that all DNA is made of just 4 chemicals. These are called A, G, C, T (for Adenine, Guanine, Cytosine, Thymine), and the whole genetic code for a person can be stored as a (rather large) collection of books with those 4 letters repeated again and again. 

Three of these letters together (called a codon) are enough to send a message to your cells. In fact that seems to be how the DNA is read, three letters at a time. Just like how a computer reads bytes, which is a group of eight 1s or 0s. There are 64 different 3-letter combos (4 x 4 x 4). 61 of these create molecules (amino acids) and the other 3 mark the end of a protein.

You can also think of it in terms of lego. Each codon (three letters) causes the cell to make a different brick, these all stick together in a specific way until you finish with your toy. Except the bricks are called amino acids and the toys are proteins. 

The c.35DelG that I carry is the most common mutation associated with hearing loss. Its ugly name actually describes a lot about it. The 'c' at the start means its a mutation in coding DNA  - this is DNA that is used specifically for making proteins. 'Del' means something has been deleted. In this case it's a Guanine, hence the 'G'. The 35 tells us where the deletion is - 35 codons in.
This turns the 35th codon into something called a stop codon - a 3 letter combo that basically tells your cell to stop making this protein. So it ends up just making the first part of Cx26, then stops.
This picture probably shows what normal Cx26 looks like:

And this one probably shows what my mutated Cx26 looks like:

Fairly shite isn't it? Looks like it does feck all. It is in fact completely useless. Mutations like this, that leave the protein doing nothing, are called 'knock out' mutations. Knock-out mutations in Cx26 seem to always cause hearing loss, with no other effects.
However different mutations can change how Cx26 works, and this leads to other issues. I'll look at this...... next time.


Terminology

• Nucleotide A molecule with a particular structure. The four building blocks of DNA (Adenine, Guanine, Cytosine, Thymine) are nucleotides.
• Codon A group of 3 nucleotides in a row on a DNA strand
• Amino Acid A molecule with a particular structure. They can be built through the use of codons and joined together to form proteins
• Protein One of the molecules constituting a large portion of the mass of every life form and necessary in the diet of all animals, composed of 20 or more amino acids linked into one or more long chains. Proteins include such specialized forms as collagen for supportive tissue, hemoglobin for transport, antibodies for immune defense, and enzymes for metabolism

Cx-Men: Rise of the mutants

Connexin 26 mutations are quite common in Caucasians. About 2% of the population carry them. As well as deafness, they can cause severe problems with skin, and in some cases blindness.  So why are they so common? Especially considering most of them are believed to be caused by a single person getting a mutation in the past, and passing it on (the Founder Effect).

Geneticists believe that for these mutations to be so common there must be some advantage to them. And they think they know of at least one. It's to do with the gap junctions; those paths that allow things to pass between cells, and are made from Connexin proteins. Turns out that sometimes it's better to keep the gates closed.

Ever since humans have been around, viruses and bacteria have been looking for new ways to attack us. Every single aspect of our physiology gets probed for weaknesses, or for some way them to get an advantage over our immune system. At least one of them, a diarrhea-causing bacteria called Shigella flexneri, manipulates gap junctions in our digestive tract to spread itself. And these gap junctions are made from Cx26.

It has been shown that people carrying Cx26 mutations are far more resistant to Shigellosis, the disease this bacteria causes. Shigellosis causes 700,000 deaths a year these days - imagine how bad it must have been before modern hygiene practices came along. Perhaps villages would be struck with a plague of Shigellosis , and only the carriers of mutated Cx26 genes would be left standing? A similar resistance has been seen for certain E. Coli infections, which cause similar intestinal problems and are extremely common. 

From a personal perspective, I rarely get any gastrointestinal illnesses. I had always assumed this was due to my parents' proclivity for foraging in the 'reduced to clear' aisles in Tesco's. The regular consumption of near-rancid meat had led to my steely constitution, or so I believed. Perhaps the true reason was my c.35delG GJB2 mutation.

Scientists have also noticed that people carrying Cx26 mutations tend to have thicker skin. It's not sure whether this provides an advantage, but skin is a barrier to infection, so who knows?

The theory that having one copy of seemingly bad genetic mutations can actually work out for you is called 'Heterozygote advantage'. For example, carriers of the mutation that causes Cystic Fibrosis are resistant to the effects of cholera, and carriers of the mutation that causes Sickle-cell anemia are resistant to Malaria. There's an article on it here if you want to know more.