David has a terminal deletion of chromosome 22 caused by a balanced translocation. Like nearly everyone with 22q13 deletion syndrome, he is missing a lot more than one gene. What, exactly, does that mean?
DNA and genes
Each gene is made up of many “bases”. DNA has two strands (strings) that grip each other tightly. Imagine a bunch of magnets threaded onto a string like pearls. Now make two of these in your mind and hold them near each other. Slowly bring them close together. When they get near, the north poles of magnets from one string will start to find the south poles from the other string. When the magnets come together, opposite poles will grab each other. Anywhere north faces north, or south faces south, that pair will repel each other until one flips around and the opposites unite. DNA is made of chemical strings that have opposite poles. These opposites find their mate and the two DNA strands lock together. Each time a north meets a south you get a “base pair”.
Magnets can only make one type of partnership (north attracted to south). DNA actually has two kinds of partnerships from four chemical bases. The bases are abbreviate T, A, G and C. T and A attract each other. G and C attract each other. If you make a string like this: -T-A-G-G-C-A-, the matching string will always look like this: -A-T-C-C-G-. That is, the strings stick to each other in this way:
Voilà! You have a small strand of DNA. This miniature DNA has 6 base pairs. The order of the base pairs describe the protein that this segment of DNA makes. The lower strand is kind of mirror of the upper strand. If you know what is on one strand you can always figure out the other strand. Thus, we now know a bunch of properties of DNA: 1) The sequence of base pairs describes how to make a protein, 2) DNA is strongly stuck to itself, 3) DNA keeps a mirror copy of itself available at all times, and 4) the length of the DNA can be measured by counting the number of base pairs. There is a lot more to learn about DNA, but this is enough to discuss gene size.
Big genes are easier to find
In a previous posting I explained that 95% of all people with 22q13 deletion syndrome are missing at least 1 Mbase from their chromosome (see Understanding deletion size). 1 Mbase means 1,000,000 (1 million) base pairs along the two parallel strands of DNA. Genes are segments of the long strings, like chapters in a book. And, like many books, some chapters are long and some are short. There are 32 genes in the distal 1 Mbase of 22q13, many of which influence brain function. Chromosome deletion syndromes are inherently difficult to study because so many genes are involved. It is hard enough to study and understand the impact of losing a single gene. It is much harder to study and understand 22q13 deletion syndrome, where many genes are missing.
This problem with studying multiple genes is not unique to 22q13 deletion syndrome. It shows up in neuropsychiatric disorders like autism and schizophrenia, each of which have hundreds of associated “risk factor” genes. Autism, for example, results from various combinations of these many genes (see review by Gratten et al., 2014). Chromosomal deletions are known to operate in a similar way (see contiguous gene syndrome). Each missing gene weakens the normal operation of the brain. No one gene needs to be “dominant” for the combined loss to be devastating, especially when so many brain-related genes are missing at once.
Not everyone thinks of 22q13 deletion syndrome this way. Much of the current thinking about the genes lost in 22q13 deletion syndrome focuses on one or two genes that code for synaptic proteins. The term “synaptopathy” has been used a lot recently, but that word originates from the study of the inner ear where they are able to clearly demonstrate the relationship between synaptic function and hearing loss (Sergeyenko et al., 2013). The same does not hold true for 22q13 deletion syndrome. Synapses are involved, but the synapse may not be the primary site of dysfunction (see Is 22q13 deletion syndrome a ciliopathy?). For many years no one thought primary cilia were important. Now, ciliopathies are a recognized type of brain dysfunction despite the fact that synapses are also involved. Science often goes off in a wrong direction; it is part of the process.
There is another reason that synaptic genes have taken the spotlight. The synaptic genes of 22q13 are relatively large genes. Defects of these genes are simply easier to notice. If we look at the history of 22q13 deletion syndrome, the first cases were discovered in people with very large deletions and with the most “severe” phenotype. As the research in 22q13 deletion syndrome advanced, smaller and smaller deletions were identified and studied. At the moment, the only gene getting any attention is a large gene that has a large effect when mutated, even though mutations do not necessarily tell you what happens when a gene is deleted (see When missing a gene is a good thing). So, why does size matter?
The pie chart shows the 32 genes missing in 95% of patients with 22q13 deletion syndrome. They are in order of size. The largest gene is SBF1 and the second largest is SHANK3. The genes continue in descending order of size in a counter-clockwise direction. Although the reality is a bit more complex, it is generally true that the likelihood of a gene mutation depends on the gene’s size. This pie graph shows that the 10 largest genes account for half of the “protein-coding” DNA in the first 1 Mbase. To put it another way, you are twice as likely to incur a mutation of SHANK3 than incur a mutation of MAPK8IP2, simply because SHANK3 is twice as large. SHANK3 is 16 times larger than SYCE3. So, when studying mutations, SHANK3 can show up more often simply because it is big.
As I noted above, no one knows what a complete deletion of SHANK3 might do on its own. A gene can have a severe phenotype when mutated, but might do little or no harm when missing altogether. SHANK3 may have some contribution to 22q13 deletion syndrome, but its relative contribution is very poorly understood. There are other 22q13 genes that have severe consequences after mutation, usually when both copies are mutated. We have discussed some of these previously (Can 22q13 deletion syndrome cause cancer?, Can 22q13 deletion syndrome cause ulcerative colitis? and Is 22q13 deletion syndrome a ciliopathy?). Another gene is SBF1, which causes Charcot-Marie-Tooth disease type 4B3. The phenotype includes intellectual disability. MAPK11 and MAPK12 are involved in responses to oxidative stress, and are likely important to recovery from infection and brain trauma. SBF1 is large, but MAPK11 is much smaller. SCO2 is one of the smallest genes, yet it is implicated in a series of severe, including fatal, syndromes (DiMauro et al., 2012). What happens when all of these genes are deleted together? You get 22q13 deletion syndrome.
The take-home message is that certain genes are more likely to come under the microscope (literally and figuratively) simply because they are larger genes. Being large makes a gene easier to study (usually), but it does not necessarily confer importance. When a gene gets popularized in the scientific literature, lots of papers are published on that one gene, at least for a while. Scientists will focus on genes that get them grants and publications. That is how science typically works, even if it is not necessarily the best approach to finding effective treatments that families really need. The direction of science can be influenced by patient groups, but choosing the right direction requires a deep understanding of the science (the current state of research), science (the discipline) and scientists (who do science).
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction