CASK gene for beginners

What is the CASK gene?

CASK is the name of a protein (a molecule that 'does stuff') found in the human body. The CASK gene is the section of DNA that codes for the protein (has the recipe on how to make it). The gene is very large, being 404,253 bases (letters) long. To put it into perspective, the average size of a human gene is 28,000 bases (Bionumbers).

The CASK protein plays an important role in the brain, allowing brain cells (neurones) to work properly. It also interacts with a number of other proteins and genes involved in the brain, making its role wide-ranging and important.

CASK — the Swiss army knife of proteins

The CASK protein is a large protein that can do many jobs. It is best to think of it as a swiss army knife. Depending on the mutation, the swiss army knife can do all of its jobs, most of its jobs, a few jobs, or none of them.

Types of mutations

The most serious mutations tend to be deletions. This is when a letter has been deleted in the gene. It generally means that some or all of the tools on the knife are broken. If you have been told that your child has a frameshift mutation, this will have been the result of a 'letter' in the DNA being accidentally deleted or added. This shifts the genetic "reading frame", causing the instructions after the change to become scrambled. This usually leads to little or no working CASK protein being produced. Frameshift mutations are often associated with MICPCH and more severe symptoms.

A duplication is when a portion of the gene is duplicated within or at the end of the gene. This can mean that a few of the tools are damaged, but not broken. Maybe a knife got a bit rusty or the corkscrew a bit bent. So it can still do the job but it may struggle, be inefficient or just be a bit 'hit or miss'.

Your geneticist may have told you your child has a missense mutation. A missense mutation is a small spelling change in the gene that swaps one building block of the protein for another (called a substitution). Missense mutations are more commonly associated with XL-ID or milder presentations because the protein may still work partly.

In other cases, it can have a bigger impact and cause MICPCH, since it can cause a nonsense mutation. This is a serious type of mutation since it means the knife is likely to be completely broken, or only has some of its tools. This is because this kind of mutation has caused an early 'STOP' sign, meaning the rest of the gene is not 'read' and so the protein is then not made. Nonsense mutations can also be the result of deletions or additions.

Some people are found to be mosaic for the mutation. This means that the faulty genes are only found in some parts of the body. This happens because the genetic change occurs after conception during early development. People with mosaicism tend to have less severe symptoms or they can be asymptomatic. This is because some cells still contain a working copy of the CASK gene. The effects can vary greatly depending on how many cells are affected, and where.

Genes contain sections that need to be joined together correctly when the protein is made. Splice site mutations interfere with this process. They can have varying results — some cause a non-functioning protein while others still allow some protein to be produced. These mutations can cause either MICPCH or XL-ID, depending on how much the mutation disrupts the protein.

Is a CASK gene mutation inherited?

Most CASK mutations happen de novo, which means they occur for the first time in the child and were not inherited from either parent. There is nothing that the parent could have altered or done differently to avoid their child having the condition. This is good news for family planning because there is no reason any future children should have the condition. The geneticist assigned to the family should explain this (or any exceptions) and reassure the family. Nevertheless, the NHS are increasing their genetic testing tools and couples may be able to request a blood test in the early stages of future pregnancies to find out whether the same mutation has occurred again.

Why are inherited CASK mutations more common in boys?

The CASK gene is located on the X chromosome. Girls have two X chromosomes whilst boys have one X and one Y chromosome.

In girls, mutations that completely stop CASK from working often cause MICPCH because one of their two X chromosomes is affected.

In boys, having no working copy of CASK is usually extremely severe and is often not compatible with survival before or shortly after birth. Because of this, boys who survive are more likely to have mutations that still allow the CASK protein to work partly, or they may have mosaic mutations where not all cells are affected.

This is why inherited CASK mutations are more commonly seen in boys with XL-ID or milder presentations. In some families a mother may carry a mild or mosaic CASK mutation and pass it on, or the mutation may be inherited through several generations.

Genetic counselling can help families understand inheritance patterns and recurrence risks for future pregnancies.

The CASK gene in different sexes

CASK gene mutation is an X-linked disease. This means that the gene is found on the X chromosome and so boys and girls will be affected differently.

All boys' cells contain an X and a Y chromosome (along with 22 pairs of other chromosomes). Girls' cells contain two X chromosomes. Since the CASK gene is found on the X chromosome, girls have two CASK genes in every one of their cells. One will be functional and the other will be faulty. The body automatically inactivates one X chromosome in each cell, but this is completely random as to which X chromosome gets inactivated. On average it means that, in girls, 50% of their cells have the healthy CASK gene activated (and so can make a perfect CASK protein), and 50% of their cells have their faulty gene activated.

Boys' cells only contain one X chromosome, and therefore only one CASK gene per cell. Therefore, if they have CASK disease, they have no healthy copy of the CASK gene in any cell. Sadly, this means the child is very sick and normally passes away soon after birth.

There are, however, exceptions and there are a number of boys in the world with CASK gene mutation who, possibly due to mosaicism (Burglen et al. 2012), have a mild version of the condition.

MICPCH and X-linked intellectual disability

The brains of children with CASK gene mutation often fall into two categories. From an MRI it can be seen that the cerebellum is underdeveloped, causing the microcephaly associated with the disease. If the pons (part of the brain stem) is also small or misshapen then the child is said to have pontocerebellar hypoplasia (PCH) and, specifically, MICPCH. This is the more severe form of the disease. If the brain stem is healthy then the condition is called XL-ID.

Not every child fits neatly into one of these two groups and some specialists see it more as a scale, with MICPCH associated with intractable epilepsy at one end and XL-ID at the other.