Understanding the Genetics of Kabuki

Every cell in our body contains a full set of chromosomes and identical genesi. What then differentiates our cells? What makes some of our cells become muscle and others, say, skin? This happens because only a fraction amount of genes in each cell are 'turned on' or 'expressed'. That’s an interesting concept isn’t it? That our blood, hormones, bones, and heart all share the exact same building blocks (genes), but only a select few are turned on in each system!

Most of us don’t have an insatiable desire to understand genetics, but we all have some basic curiosity as to DNAwhat our bodies are made of. How does it all work? This is particularly true when things don’t work so perfectly.

Let’s begin with the smallest most basic elements of the body – DNA. DNA is made up of 4 bases (adenine, cytosine, guanine, and thymine), each represented by the letter which they begin with. The bases pair with one another and are attached to sugar and phosphate molecules to make what looks like a ladder. See Figure 1.

A gene is a length of DNA ladders.  We have approximately 25,000 genes. The DNA ladders make up a code, similar to our alphabet. Actually, very similar to our alphabet. They are read 3 letters at a time to produce amino acids. Think of the amino acids like the words of a sentence. They are read similarly to the way we know that the letters a-r-m signifies a part of the body. These same letters put in a different order, r-a-m, now represents a male sheep. Since there are four different letters (A, C, G, and T), there are 64 different combinations that can be used. However there are only approximately 20 amino acids. That means that different codes can produce the same amino acid. Some of them act as punctuation for the sentence, signalling when a sentence begins and when it ends. See Figure 2 

An example of an amino acid chain might be: CAT ATT GCA GAT TGT

Use the DNA decoder wheel below to find out what your amino acid chain would look like. Start from the inside of the wheel and work outwards to the second ring for your next letter and so on till you get to the outside ring to find the name of your amino acid.


You should have decoded: Histidine-Isoleucine-Alanine-Aspartic Acid-Cysteine

Proteins are made up of many amino acids. Think of them as the sentences. It is these proteins that perform most of the critical functions of each cell. Again, some proteins will form muscle, some will work as enzymes to regulate hormonal and other chemical processes, and yet others will regulate the genes themselves.

Only about 1% of our DNA is coded by genes, which in turn make proteins. The rest is referred to as non-coding DNA and is not yet well understood. It is believed, among others, that they have an influence on our cells to know when to switch certain genes on and off.


Chromosomes are made up of many genes. Humans have 22 pairs of chromosomes plus one pair that determines our sex. Seechromosome Figure 3

Let’s re-cap: DNA consists of 4 bases, and sugar and phosphate molecules to form ladders. Genes consist of DNA ladders and it’s all tightly packaged into bundles called chromosomes.

DNA is read 3 bases (letters) at a time to produce amino acids (the words) and stops and starts (punctuation). Many amino acids make up proteins (the sentences) which are contained in genes (paragraphs or chapters). Proteins do the work in constructing our bodies (which makes the story complete!)

So what happens in the case of disease or a syndrome? Sometimes one of the letters of the DNA is swapped for another. All of us carry some of these errors. So why do we not all have a syndrome? Remember how the four DNA letters could be coded in 64 possible combinations (4x4x4x4) but will only produce about 20 different amino acids? Some combinations can handle an error. For example if the letter T is swapped for an A in the codon GCT the resulting protein would still be the same, since both the old codon (GCT) and new codon (GCA) code for the same amino acid (see for yourself with the DNA decoder). Other error combinations may have very serious effects. Swapping an A for a T in a gene for haemoglobin results in the serious blood condition sickle cell anemiai. Think of it like this: it's OK if Jane the waitress doesn't show up because we can move Mary into her position and Jack into Mary's position since they have all performed each other's tasks. However if Jessica the orthopedic surgeon doesn't show up, we can't very well have the OR nurse fill in for her! Other errors can occur as well, such as a bit of the DNA sequence is missed or a bit added, etc.

Karyotyping or blood chromosomal analysis is a study of our chromosomes. Cells are stained and examined microscopically to examine the size, shape and number of chromosomes in the sample. Think of it as a view of earth using a satellite. It will clearly show if a continent or country has changed its shape.

Microarray analysis allows scientists to scan the chromosomes, looking more closely at the genes. Different types of microarrays are able to detect different things, for example if there are insertions or deletions of genetic material or compare the expression of genes (remember, this means whether the gene is 'turned on' or not) in a healthy sample versus a diseased one. Think now of a more powerful satellite image that gives you the ability to see cities.

Targeted gene sequencing allows scientists to look very closely at our DNA to detect small changes in the sequence, or ‘letters’ in the DNA. Think now of a satellite so powerful that is able to see single homes.

Most individuals with Kabuki will have normal chromosomal study test results. The ‘error’ is in a letter – a home, not a continent. Even though the change is ‘small’, that is not to be misunderstood as being a minor error – just a difficult one to see until recently. Increased ability to see smaller and smaller elements of our body and increased understanding of what those elements do, make it possible to more accurately diagnose conditions. But science is a continuous process - one discovery and level of understanding leads to another. Much still needs to be understood, which may even lead to prevention in the future. These are exciting times in the genetic world!

In the case of Kabuki, mutations of the MLL2 gene has been found to occur in 75% of individuals who have been subjectively diagnosed with Kabuki. They were found to be due to either nonsense or frame-shift mutation which resulted in a shortened, nonfunctional protein. A nonsense mutation is a change in one DNA base pair. The altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all. In the example below, you can see how the insertion of the base thymine (T) is now read as TAG instead of the intended CAG. Since TAG is read as a STOP, the resulting protein is shortened. Refer back to the DNA Decoder Wheel to see how this happens. A frameshift mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations. In the example below you can see how the shift of the first DNA base means that the succeeding bases are all read incorrectly.   

nonsense            frameshift

More specifically in the case of Kabuki  Addition by Maggie McMillin, Clinical Research Coordinator at University of Washington

A genomei is an individual’s entire genetic code. The Human Genome Project was the first time scientists had completely looked at every base (letter) of the genome. There are about 4 billion bases in the entire genome. It is still very difficult and very expensive to sequence an entire genome.

Only about 1% of the genome contains genes. There are about 20,000 genes in the genome. An exomei is a newly made-up word to describe targeted sequencing of all the genes. Remember that genes are the part of the genome that code for proteins, and proteins are the things that perform functions in the body. If something does not function or develop properly, a gene is the first place to look to find a change that might cause the disease or dysfunction. So exome sequencing is a way to focus on looking at the most important part of the genome. And because there is much less sequencing than looking at the entire genome, the cost is much less.

Recently researchers studying Kabuki syndrome at the University of Washington and Seattle Children’s Hospital used exome sequencing to identify the gene causing the syndrome. In the study, researchers sequenced the exomes (all the genes) of 10 individuals with Kabuki Syndrome. Then they compared the information between all 10 individuals to find a gene that contained a change that would be predicted to cause dysfunction of the protein. They found the MLL2 gene (now referred to as KMT2D) that had changes, or mutations, in 9 out of the 10 individuals. Then researchers used targeted sequencing to look at the same gene in more individuals with Kabuki and about 75% of individuals had a change in the gene. The gene provides the instructions, (like a recipe) to make a type of protein called a histonei methyltransferasei. Histones are proteins that the DNA is tightly wound around, like a spool of thread. This helps to package all the DNA so that it can fit inside the cell nucleus. When a cell needs to “read” the DNA to make a protein and perform a function, it unwinds whatever little part needs to be read. Histone methyltransferase is type of protein, called an enzyme that helps to unwind the DNA from the histone.

There are two clues as to why this gene is a causative agent of Kabuki:

  1. The individuals without Kabuki (control individuals) do not have the same types of changes in this particular gene.
  2. The parents do not have the change (unless they also have Kabuki). So most of the time the change in an individual with Kabuki is a new, “sporadic” change. This is just something that happens by chance.

This means that researchers have identified the MLL2 gene that explains a large number of cases of Kabuki syndrome, and now a clinical test can be developed. For individuals with Kabuki that do not have mutations, there is likely another gene that causes the syndrome. The researchers are still conducting the study to look for other genes. (Update: mutations of the KDM6A gene have since been discovered in 9% of individuals who tested negative for MLL2 gene mutation.)

It’s not yet known how the changes to the gene change the function of protein or why it causes the features of Kabuki syndrome. It’s also not known if different changes within the gene can lead to more or less severe clinical features. But now that the gene has been identified, scientists have the next step in moving forward to try to answer these questions.

Copyrighted 2010

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