Science is really interesting if you don’t let the details overwhelm you. Scientists master huge piles of details, but they always step back to see the big picture. They are truly fascinated with science. That fascination motivates their quest. In this blog I will point out some really interesting facts so you can share that fascination.
This blog is about organelles of the cell called mitochondria. If you look at cell with a high power microscope you will see something that appears to be another tiny organism living inside the cell.
Interesting fact #1: Mitochondria may have originally been single cell organisms that invaded larger cells. Now, mitochondria are simply part of our cells.
Interesting fact #2: Mitochondria are the battery chargers of the cell. They turn sugars and oxygen into ATP. ATP molecules are the rechargeable batteries used by the cell for nearly everything – from muscle contraction to digestion, growth and thinking. Imagine what might happen if all your battery chargers were on the fritz. That would be a cell phone (mitochondrial) disorder with dramatic consequences.
Interesting fact #3: A paper published in January of this year shows that most people with 22q13 deletion syndrome have mitochondrial dysfunction (http://www.ncbi.nlm.nih.gov/pubmed/26822410). Mitochondrial dysfunction affects more kids than any other problems except for intellectual and physical disabilities.
Interesting fact #4: Mitochondria are unique organelles because they operate using two separate sets of genes. One set of genes is on the regular (nuclear) DNA. The other genes are actually inside the mitochondria. These genes, mitochondrial and nuclear, operate together.
Interesting fact #5: mitochondrial genes come only from the mother, whereas nuclear DNA is an even mix of both parents. The term “mitochondrial gene” is confusing. Sometimes it means a gene from the mitochondrial DNA. Other times it means a nuclear gene that is needed to help the mitochondria work properly. In 22q13 deletion syndrome, a group of genes on chromosome 22 (nuclear DNA) are lost. Many of these genes are important to normal mitochondrial function. These are the mitochondrial genes I will discuss now.
The following genes impact mitochondria. I have written on several of these genes previously. This list includes the minimum size of a terminal deletion that would damage or delete the gene. The list is borrowed from my earlier blog (How do I know which genes are missing?).
Mitochondria related gene
Deletion size (Kbase)
This list has 17 genes. About half the children with terminal deletions are missing 5.3 Mbases (5,300 Kbases) or more (see Understanding deletion size). That means half or more of our children are missing at least 8 mitochondrial genes. Have you met a child with a really large deletion? They generally have multiple major health issues. It is not clear which mitochondrial genes contribute the most to their problems, but even children with smaller deletions are outside the normal range of mitochondrial enzyme functioning.
Some of these genes likely have little or no impact. I have written about ATXN10 (Gene deletion versus mutation: sometimes missing a gene is better.). Some people inherit a mutated copy of ATXN10 that has an extra sequence. It is an unused sequence that gets stripped off when the protein is produced. The protein is normal. However, the excess stuff that gets stripped off interferes with another enzyme in the body. The interference ends up poisoning the mitochondria and killing the cells (http://www.ncbi.nlm.nih.gov/pubmed/20548952). Fortunately, this is not a gene we need to worry about. Our children are missing ATXN10. They don’t have the mutated gene seen in certain families. Likewise, based on what is know about the BIK gene, it is also unlikely to contribute to our children’s mitochondrial problems.
So, which mitochondrial genes are causing so many problems? One gene is specific for muscle function (e.g., CPT1B). We should not be surprised if that mitochondrial gene contributes to hypotonia (see 22q13 Deletion Syndrome: hypotonia). However, most mitochondrial genes are essential for normal function in every part of the body.
We know that more than half of our kids are outside the normal range of mitochondrial function. Many scientist believe that mitochondrial genes contribute to neurodevelopmental disorders (http://www.ncbi.nlm.nih.gov/pubmed/26442764), and that those disorders (e.g., 22q13 deletion syndrome) are associated with mitochondrial dysfunction (for example, http://www.ncbi.nlm.nih.gov/pubmed/26439018). What is needed now is a more complete study that includes all of our children. How? When the scientific paper came out in January describing mitochondrial dysfunction in our children, I was certain the researchers would be invited to the 2016 conference. The head of that study was eager to come, present his results and gather more cheek swabs. What happened?
There have been a number of press releases and feel-good articles circulating among my 22q13 deletion syndrome Facebook friends celebrating the advancement of mouse models of “Phelan McDermid syndrome”. I am all for enthusiasm! However, cheering is more fun if you know how the game is played and what to cheer for. With that in mind, I would like to look carefully at models. What is a good model and what might it tell us?
I started out in engineering, where modeling is very important. Let’s imagine modeling an airplane. The first issue of modeling is, what aspects of the plane are motivating us to build a model? In this case we might want to learn about how the airplane will perform if the tail is damaged in flight. We can construct a scaled-down miniature with wings, tail, etc. and omit the inside furnishing (cockpit, storage compartments, etc.). If the miniature has the exact same shape and moving wing/tail parts as the real airplane, we would say our model has construct validity. That is, it is constructed in a way that reflects the original plane. The next step is to put our model into a wind tunnel and see if it flies. The model is held on a wire. We can adjust the wing flaps and other control surfaces. If the model tries to rise at the same wind speed as the real plane, and tries to bank left or right with the same amount of wing flap adjustment as the real plane, we can say this model has face validity. That is, with regard to what we are testing, the model behaves much like the real plane. We are finally ready to benefit from all our work. Let’s take the model for a test flight and then poke a hole in the tail. What settings of the flaps and other control surfaces allow us to keep control of the plane? We may struggle with this for weeks or months hoping we can learn to control our crippled model plane. If we find a solution, maybe we have found a way for pilots to rescue their plane in the event of a similar emergency. If this scheme works, our model has predictive validity. Thus, we measure a model’s worth by:
does it model what we want?
is it constructed in a way that tests what is important to us? (construct validity)
does it perform in a way that mimics what we already know? (face validity)
will model manipulations tell us how the real thing will respond? (predictive validity)
I hope you are getting a picture of what an animal model should do. Let’s look at a mouse model of “Phelan McDermid syndrome” or “PMS”. I use quotes because different scientists have different definitions of “PMS”. See Introduction. For this blog, I will omit the quotes, but remember that there are numerous definitions floating around.
The definition of PMS is important for modeling. The definition of PMS tells us what people claim to be modeling. Some scientists define PMS as a deletion or mutation on chromosome 22 that involves SHANK3. That is fine with me, but that omits the rest of 22q13 deletion syndrome, since there are numerous cases of “interstitial deletions” that don’t affect SHANK3. So, SHANK3 might not be a good choice of model for many families. It depends on the deletion and it depends on what is causing your child the greatest difficulties. There are currently mouse models for 11 different PMS genes for deletions of 1 Mbase or larger. Every gene on this list is relevant to 95% of patients (See Understanding deletion size.) The 11 genes are BRD1, CHKB, CPT1B, MAPK8IP2, MAPK11, MAPK12, NCAPH2, PANX2, PIM3, SHANK3, TYMP. Most of these mouse models are very well studied. If you go further up the chromosome you find other well studied genes with mouse models, like ATXN10. So, the choice of gene is all about what aspect of a disease or syndrome you wish to study.
SHANK3 is popular not because of PMS. It is popular because is has been associated with autism. There are under 1,000 identified people in the USA with PMS, but there are an estimated 36,500 children born each year in the USA with autism. Parents of 22q13 deletion syndrome children should appreciate that researchers who study Shank3 mice are tapping into the national (and world) autism crisis. Our children are a convenient source of subjects, which is why the big national study officially excludes PMS families with interstitial deletions that do not affect SHANK3. Children with SHANK3 mutations are of greatest interest even though they technically do not have 22q13 deletion syndrome (that is why the name PMS was created). Note that only 1/3 of children with PMS have autism, so patients with SHANK3 mutation and autism are the most valuable research subjects.
Although SHANK3 is of great current interest, autism is caused by hundreds of genes. Most parents don’t realize that many 22q13 genes are autism-related or suspected to contribute to autism. Some of the autism genes on chromosome 22 are BRD1, CELSR1, CHKB, MAPK12, PANX2, BRD1. Further up the chromosome (associated with somewhat larger deletions) you can find CELSR1, WNT7B, TCF20, EP300 and others.
Now we understand that Shank3 mice need to be models of something. From the above lists of genes, it is pretty clear that a mouse missing only one gene is not a universal models of either 22q13 deletion syndrome or autism. Both conditions involve a large number of genes. The Shank3 mice are single gene models. The mice are fashioned after super-rare cases of people with specific SHANK3 mutations. Let’s see how these models stack up in terms of construct, face and predictive validities.
All of the published papers so far describe Shank3 mutations and microdeletions, not deletion. I am not going to cite the specific papers here. I have written brief reviews on most of these papers. Contact me if you would like specifics. Some of the mouse Shank3 models use deletions that reflect mutations found in actual patients. For those specific patients (often just one or two), the genetic manipulations have construct validity. That is, the mouse gene has been changed in a way very similar to the human gene. As for the rest of us PMS parents, 95% of our children are missing the SHANK3 gene altogether, along with 30 to 100 more genes. So, these mice do not have very strong construct validity for our children. It is well known that mutations can be very different from deletions. (see Gene deletion versus mutation.) Of course, mutating a single gene may not be very helpful to understanding your child when so many other important genes may be involved. (see How do we know which genes are important?) There is also the problem of using a mouse to model a human. The gene is mutated in an animal that lacks brain areas that are crucial to human behavior, like the granular prefrontal cortex. If these brain areas are important to autism, then the construct validity is weaker.
To be fair, a lot of work goes into to creating a knockout mouse. I don’t have first-hand experience, but I work down the hall from a colleague who is an expert. He works hard and I can read the frustration in his brow on tough days. Just making a mouse is not good enough, you have to prove you have modified the right gene in the right place without messing up the rest of the genome. Then you cross-breed, back breed and then do more validations. My hat is off to those people who make a living this way. When done, the mouse has construct validity in that the targeted gene has been modified.
Face validity is a huge problem with mouse models. Our model airplane ascends and descends, banks and aerodynamically behaves much like its real-life big brother. We know the flight behaviors that are important and we can directly (although not perfectly) compare our model plane to the real thing. How do we compare our model disease to the real disease? Generally, the first step is to compare normal mice to our genetically modified mouse. We note what is different between the two. Then, we compare normal human subjects (“developmentally typical”) to those with the syndrome or disorder. The question then becomes, do the mouse differences seem to reflect the human differences? Mouse models of kidney function and cancer have been very successful with face validity. Urine output and tumor size are easier to measure than social behavior and eye contact in mice. Biopsies of human kidney and many tumors are also much easier than brain biopsies. It is no surprise, then, that mouse models of neuropsychiatric disorders are hard to validate.
The differences between normal and mutated mice can be observed in brain structure, chemical signatures, cellular changes and gene expression. For the most part, there is very little human data for comparison. There are studies with human post mortem tissue that can be helpful, but most of that tissue is from normal human brain. As you might guess, screening for gene expression and other changes in a donated brain from a PMS patient will have issues. Most patients have too many genes involved. One helpful approach is induced pluripotential stem cells (iPScs), grown from skin samples or hair follicles. One might even be fortunate enough to find a donor who’s genetic mutation matches the mouse (or vise versa). However, iPScs do not undergo normal development, so developmental studies are impossible at the moment. They also don’t produce circuits like an intact brain. These are all limitations that impact face validity.
The one common feature you can examine between mice and humans is behavior. There are two extreme viewpoints in this regard. At one extreme, some scientists argue that any behavioral difference between the normal mouse and the genetically modified mouse is “autism-associated” because of the construct validity. At the other extreme, a few scientists argue that the mouse behavioral difference should reflect the standard manual that defines neuropsychiatric disease (DSM-5). The remaining scientists are in the middle until it comes to publishing a paper. Then, they make the argument that their animals’ behavior somehow reflects the behavior of a person with autism. It is my observation that the more popular or prestigious the journal, the more their mouse sounds like a miniature human.
A major problem with Shank3 mice is that, almost universally, they don’t have a significant aberrant behavior. How can you study behavior when it seems normal? There are two solutions, but both have problems. With one approach, researchers find a mutation spot on the gene that is extra good at producing a pathological behavior (e.g., ignoring other mice, not learning, rubbing its fur until the skin is damaged). Another approach is to mutate both copies of the gene. Each of these solutions creates a new problem. In the first case, we are no longer modeling PMS or autism, because this behavior only shows up in very specific mutations. In the second case, we have lost construct validity. We were never trying to model mutation or loss of both copies of SHANK3. That would likely be a different syndrome (just as mutation is different from deletion).
In the end, current models of SHANK3 mutation (autism and SHANK3 mutation aspect of PMS) provide information about molecules and neurons, but are very limited models of the human diseases. They don’t necessarily say much about 22q13 deletion syndrome in general. It is interesting to note that mouse models of other genes of 22q13 deletion syndrome may be more promising. Several mouse models have clear consequences with only one gene mutated or deleted. For example, the Cpt1b mouse model is used to study cold tolerance and insulin sensitivity, and the autism and schizophrenia-associated gene, BRD1, is under intense research right now by a group in Denmark. In both cases the behavioral effects are clear when only one copy of the gene is affected.
We are not done yet, because the most important and most difficult type of validity is predictive validity. That is, does your mouse model tell you what will happen in your human subjects? Given all the problems with making a mouse model of a neuropsychiatric disorder, it is no surprise that the models have not lead to translational (treatment) gains. (See Hope for autism treatment dims as more drug trials fail).
I have heard many people in the research field try to sound hopeful to parents. I believe that hope, when anchored in reality, is very helpful and important. But, too many people have alternative reasons for fanning the flames of hope by knowingly or unknowingly misrepresenting the size of strides in research. My recent blog (How can the same deletion have such different consequences?) touches on why so many parents are mislead by researchers, writers and support organizations. The subsequent blog (22q13 deletion syndrome and science leadership) explains that it does not have to be this way if we bite the bullet and hire qualified leaders.
As a parent, my heartstrings feel the tug of hope every day. The urge to follow those feelings is managed by having a deeper understanding of the research world, and remembering that too many people are eager to give those strings an extra tug.
Although he is a bit unsteady at times, David loves to walk. When he first started his day program, the aid assigned to him nearly gave up. Keeping up with David’s constant motion — walking — forced her to become an athlete. She looks back at the experience now in an appreciative way. David brought fitness into her life and the two of them have a deep affection for each other. They have enriched each other’s lives in very deep ways.
Having very low muscle tone interferes with normal growth and development in many ways. Muscle tone is important for breathing in newborns (Lopes et al., 1981). David was born prematurely and he was on a ventilator for weeks. Low muscle tone slowed his recovery. Muscle tone is important for normal cognitive development and function (e.g., Jongsma et al., 2015). Gastroesophageal reflux plagues many children with 22q13 deletion syndrome (including David) and is likely caused by low tone in the esophageal sphincter (Hershcovici et al., 2011). The most obvious problem with low muscle tone is delayed or absent walking. Walking requires stable standing, which requires sufficient tone to hold the body erect. Building strength in David’s abdominal, back and leg muscles was years of work.
What is muscle tone and what interferes with normal tone? “Muscle tone refers to the resistance that an examiner perceives when moving someone’s limb in a passive manner” (Mitz and Winstein, in Neuroscience for Rehabilitation, 1993). Normal muscle tone disappears when someone is knocked unconscious, or when the muscle itself is unable to support contractions. Diagnosing the cause of hypotonia in infants can be complex, especially in the presence of a genetic syndrome (Bodensteiner, 2008). In genetic syndromes that include both hypotonia and intellectual disability, the hypotonia is often diagnosed as “central hypotonia”: hypotonia caused by problems with the brain or spinal cord. However, the hypotonia associated with 22q13 deletion syndrome may be from multiple causes. Certainly, it is not caused by any one gene. No single gene deletion or mutation has been identified that always causes hypotonia, and no one gene is essential to cause hypotonia. There is also no doubt that infant hypotonia is far more common in children with somewhat larger deletions (Sarasua et al., 2014, figure S1).
The severe hypotonia so often seen with 22q13 deletion syndrome infants comes from multiple sources. Since finding a way to treat hypotonia could help 100s of our children, understanding all the causes might open the door to improving their lives.
Genes that directly affect synapses
If your child was seen by a pediatrician or pediatric neurologist, it is likely the physician concluded that the hypotonia was of central origin (see, Bodensteiner, 2008). Although the conclusion would be based on accepted clinical practice, it would actually require a battery of tests to rule out other sources. Without other signs of major muscle or metabolic problems, the physician may be wise to avoid additional tests. Right now, such testing is best done as part of a research study.
One obvious source of central hypotonia is a problem with synaptic proteins. Two important proteins coding genes nearly always deleted together are SHANK3 and MAPK8IP2. I have found only one published clear case where MAPK8IP2 is deleted without SHANK3 (Vondráčková et al., 2014). That patient had hypotonia, but another important gene was involved (SCO2, discussed later). There are also very few cases of SHANK3 deletions without impacting MAPK8IP2. I am not considering SHANK3 mutations, since we know mutations can be much more severe than deletions. See my earlier blog: When missing a gene is a good thing. For those who wish to consider SHANK3 mutations, we know that hypotonia with SHANK3 mutations is much less prevalent (33%) than hypotonia in 22q13 deletion syndrome (65% to 75%), whether or not SHANK3 is involved (Vondráčková et al., 2014). Thus, synaptic genes may play a role, but the jury is still out on how important they are to hypotonia.
Other genes that affect normal function of the brain
Hypotonia of central origin can be caused by other genes important to brain function. We sometimes forget that the brain must have lot of things working properly for synapses to operate. For example, the brain is about 2% of our total body weight, but it uses up 20% of the oxygen we breathe (Rolfe and Brown, 1997). So, the blood flow from the heart, nutrition from the gut and oxygen from the lungs are of critical importance to human brain function. Any missing gene that might affect the brain’s ability to burn energy will likely impact synaptic function. Note, this raises an important limitation of studies that use rats and mice. Rats have very small brains and only use 3% of the oxygen they breathe for the brain. They are not nearly as sensitive to the “energetics” of brain function.
SCO2 and TYMP are genes that are important in making full use of nutrients, oxygen and blood flow to maintain healthy synaptic operation. One copy of these genes is missing from nearly everyone with a terminal deletion. You may recall that humans and other animals normally have 2 copies of every gene. People missing just one copy of SCO2 or TYMP seem to do fine (Pronicka et al., 2013). I found a paper that investigates the role of SCO2 and TYMP in patients with an interstitial deletion of 22q13 (Vondráčková et al., 2014). The authors describe two children who are not only missing these genes from the deletion, but, tragically, the remaining gene (on the other chromosome) is mutated. That is, both copies of the gene are affected. One child has a mutation of his remaining SCO2 gene. The other child has a mutation of the TYMP gene. One child died before age 2. The other is 12 years old and is going downhill. Over 95% of children with terminal deletions of 22q13 are missing one copy of SCO2 and one copy of TYMP. We do not know how much these genes contribute to infant hypotonia in 22q13 deletion syndrome, but if a child has a life-threatening failure to thrive, he or she should be tested for SCO2 and TYMP mutations. There are potential treatments (Casarin et al., 2012; Viscomi et al., 2011).
Unfortunately, there are many genes deleted in 22q13 deletion syndrome that might impact normal brain function. My earlier blog pointed out that 95% of people with 22q13 terminal deletions (including ring 22) are missing at least 10 genes that operate in the brain (Understanding deletion size). ALG12 is a gene critical for allowing cells to recognize each other. Loss of both copies of ALG12 produces a severe disorder (CDG-Ig) that can include hypotonia, as well as moderate to severe intellectual disabilities and seizures. Loss of one copy by itself is not pathological, but loss of ALG12 along with other genes could have a big contribution to hypotonia. CELSR1 is an example of a gene that could worsen the impact of ALG12. We know that larger deletions are more likely to cause serious hypotonia (Sarasua et al., 2014, figure S1). CELSR1 is associated with deletions larger than 4.5 Mbase. CELSR1 along with ALG12 is a one-two punch to the development of normal synaptic pathways. Both are important for the intricate organization of brain cells during early development. What about a 1-2-3 punch? I have already discussed RABL2B (Is 22q13 deletion syndrome a ciliopathy?). RABL2B is used in primary cilia, which are also responsible for guiding neuronal organization during early brain development.
There are other genes deleted in 22q13 deletion syndrome that are important to maintain healthy brains. I will cover some of these in future blog postings. However, I would like to look now at genes that might act outside the brain to cause or exacerbate hypotonia.
Genes that affect the muscles
It is probably no surprise that hypotonia can come from problems with the muscles. Muscle cells share a lot in common with the neurons of the brain. They rely on electrical activity, they have a junction with the nerve that is very much like a synapse and they require lots of blood flow and energy. Sitting very near the synaptic genes and missing in over 95% of children with 22q13 deletion syndrome, is a gene that is crucial to the energy supply of muscles, CPT1B. CPT1B is like the shovel for an old coal-burning steam engine. It grabs the coal and throws it into the steam-engine’s firebox. Technically, it helps transport fatty acids into the mitochondria for the generation of ATP. ATP interacts with muscle actin and myosin to power muscle contraction.
Genes that affect the nerve fibers leading to the muscles
SBF1 is one of about 70 genes associated with Charcot-Marie-Tooth (CMT) disease. (CMT has nothing to do with teeth. It is named, in part, after Howard Henry Tooth.) CMT is a demyelinating disease (Baets et al., 2014). Myelin is a fatty tissue that wraps around the nerves. It is the insulator that makes sure electrical signals traveling down the nerve fibers reach the muscles quickly. Demyelination, the loss of myelin, leads to weakness and muscle dysfunction. CMT is a degenerative disease. It usually appears in the 20s and starts with leg weakness. How the loss of SBF1 might interact with other genes lost with 22q13 deletion syndrome is not known. SBF1 may not contribute to infant hypotonia, but it is something to consider if weakness starts to occur early in adulthood. Like many of the genes described here, SBF1 is missing in over 95% of patients with 22q13 terminal deletions.
I have provided just a few examples of genes that are known to be involved in hypotonia. In my own review of the genes of 22q13 deletion syndrome, I have only looked closely at 34 of the approximately 200 genes that can be deleted. I have focused on the distal-most genes, those that affect the overwhelming majority of our children. Even looking at just this small selection, we begin to see the complexity of a chromosomal deletion. Focusing on just one or two genes may seem like a way to simplify the problem, but it steals the opportunity to understand what is happening to our children. The more we get to know 22q13 deletion syndrome, the more we can find opportunities to make things better.
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?
Genes lost in a 1 Mbase deletion of 22q13 sorted by their sizes (mRNA size).
Right click on the graph to see a full size image.
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).