What do parents want to know?

david-dressed-up
David dressed up in his birthday best

One nice thing about writing a blog is getting feedback.  While I embrace and benefit from all kinds of feedback, I admit being partial to positive feedback.  I get some nice comments from friend on my Facebook page.  I love the encouraging comments that get posted here.  There is another kind of feedback that is neither positive nor negative, but very informative.  It is the kind of feedback that we should all pay attention to.  Visitors vote with their mouse (or touchscreen).  Every time someone clicks on a blog link, WordPress adds one to a blog page counter.   Now that it is 2017, let’s see what the numbers recorded in 2016 tell us.

stats-2016
Frequency of access for all English Language pages of this blog in 2016

The most requested page is at the bottom of the graph: How do I know which genes are missing?  That is the number one question on parents’ minds.  It makes sense.  If your car breaks down, you want to know what caused it, even if you don’t know much about cars.  At the very least, you have some idea of what needs fixing.

Three more questions are virtually tied for 2nd place. Have you ever met a child like mine? and How to fix SHANK3 are discussions of SHANK3 and its relationship to the other genes of 22q13 deletion syndrome.  Together, with the most requested blog page, over one-third (35%) of mouse clicks on this blog are from people who want to understand how all the genes of 22q13 deletion syndrome operate together to produce the disorder.  The other blog page that is tied for 2nd place addresses the same topic from the opposite direction: How can the same deletion have such different consequences?

Taken together, nearly half (46%) of the information people want from this blog is to understand what genes are missing and why those genes matter.

Most visitors in 2016 already knew about 22q13 deletion syndrome.  Only about 4% of all clicks went to 22q13 deletion syndrome – an introduction. Fewer clicks went to learning about the author. (I can live with that!)  But, I think there are a other links that deserve attention.  Here is a suggestion for the new year:

Gene deletion versus mutation: sometimes missing a gene is better.
SHANK3 is not the only gene of 22q13 that can have serious consequences when mutated (modified, but not lost altogether).  Much is said about SHANK3 mutations, but 98% of people with 22q13 deletion syndrome are missing SHANK3 altogether. Understanding the difference may be crucial to finding cures.

I have dedicated the past few months to formal writing about 22q13 genes aimed at the scientific community.  That work has taken me away from this blog, but, hopefully, taken us all closer to effective treatments for our children.   That work is done for the moment and I hope to get back to this blog on a more regular basis.

arm22q13

 

Previous blogs

Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Is 22q13 deletion syndrome a mitochondrial disorder?

david-on-hike
David enjoying a walk in the park

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)
CHKB 235.47
CPT1B 240.05
TYMP 288.47
SCO2 292.86
SELO 600.85
GRAMD4 4,180.53
TRMU 4,484.77
ATXN10 4,973.16
KIAA0930 5,577.70
SAMM50 6,821.94
TSPO 7,655.23
MCAT 7,675.07
BIK 7,688.76
ATP5L2 8,177.87
NDUFA6 8,727.69
SMDT1 8,735.12
ACO2 9,289.48

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.

The degree of damage mitochondrial genes can cause can be seen with SCO2.  Loss or damage to both copies is often fatal early in life (http://omim.org/entry/604377?search=sco2&highlight=sco2).  Perhaps more importantly, loss of just one copy of that same gene reduces essential enzyme activity and leads to behavioral defects in mice  (http://www.ncbi.nlm.nih.gov/pubmed/22900024).  Thus, SCO2 could be a major contributor brain dysfunction in many children.

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?

arm22q13

Previous blogs

Educating children with 22q13 deletion syndrome
How to fix SHANK3

Have you ever met a child like mine?

How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

Educating children with 22q13 deletion syndrome

David
David is tolerant of my picture taking

If you ask me what is wrong with David, I don’t think I can answer the question without making a laundry list of problems, deficits and other issues. He has 22q13 deletion syndrome – that is what’s wrong.  Some of his problems almost killed him.  Someday, that risk may return.  In the meanwhile, his biggest problem is learning new knowledge and skills.  Can we make learning more efficient for our children?  To investigate this question, we need to understand more about how individual and groups of genes can affect the brain.

I have written blog posts on specific issues (cancerulcerative colitishypotonia) and other issues in the context of individual genes. Individual genes can impact many parts of the body.  A single gene may have multiple functions, an effect called “pleiotropy” (plahy-o-truh-pee).  We are often concerned with the primary impact of a gene more so than the secondary issues.  For example, CTFR is a cystic fibrosis gene. Its impact on the lungs is very damaging, but it also impacts other parts of the body.

Many 22q13 deletion syndrome genes are pleiotropic.  We must look carefully at all the potential effects of a gene.  Why? Because, so many genes are lost in 22q13 deletion syndrome that subtle effects can add up. When I read the scientific papers on a gene, I spend a lot of time comparing the subtle effects of this gene with all the others.  I look for cases where multiple genes have subtle effects on the same organ. By definition, 22q13 deletion syndrome is a chromosomal deletion syndrome.  It is not a monogenic syndrome as some have suggested.  I recommend using the name “Phelan-McDermid syndrome” if you want to combine SHANK3 mutation syndrome with 22q13 deletion syndrome. See: Introduction to 22q13 deletion syndrome and How to fix SHANK3.

Pleiotropic effects come in two flavors.  Either the gene has one function, but in different parts of the body, or the gene can do more than one function.  CTFR, is not a 22q13 deletion syndrome gene, but it provides a useful example.  It is the most common cystic fibrosis gene.  CTFR is involved in making secretions (fluids used in the body). CTFR mutations are most important in the lungs, but the gene also causes faulty secretions in the digestive tract, and elsewhere.

CELSR1 is a 22q13 deletion syndrome gene.  Over 40% of our children are missing this gene.  Like CTFR, one function affects many different parts of the body.  If one copy of CELSR1 is mutated, the most serious result is a neural tube closure defect (e.g., spina bifida or other spinal cord problems).  Mouse studies of Celsr1 show that it participates in helping cells organize into physical patterns so that cells can operate as a group. Celsr1 is involved in early development by organizing certain cells into functioning tissues (Feng et al, 2012).  However, the central role of CELSR1 in adult brain function was only discovered last year (Schafer et al, 2015).

During development, Celsr1 mutations can interfere with the organization of many different cells (Boutin et al, 2014). For example, ventricles are nourishing fluid lakes inside the brain. Cilia, cells with tiny hairs, line the ventricles of the brain and stir the cerebrospinal fluid (CSF) along its path through the ventricles. Stagnation of the CSF fluid is dangerous. Disordered cilia from Celsr1 mutations cause inefficient motion. In humans, stagnant CSF may have accumulating impact over years.

Very different cells with cilia are used in the ear to hear sounds. CELSR1 mutations disrupt the orientation of “outer hair cells,” responsible for hearing at low sound levels. Cilia are responsible for other body functions, as well, like keeping the airways clear and digesting food. Given its impact on different organs, CELSR1 is pleiotropic.

When someone asks me what is wrong with David, one of the first things I say is he struggles to learn.  David is aware and interested in his environment, but he knows trying to learn anything new is difficult.  My last blog discussed SHANK3 and its impact on learning that involves the ventral striatum in the brain.  Mutations in CELSR1 disrupt a different kind of learning, learning that is unique to the hippocampus of the brain.  Only two areas of the brain are able to grow new neurons.  One of these areas feeds the new neurons into the dentate gyrus of the hippocampus and has a subtle, but critical effect on learning . Mutation of rodent Celsr1 disrupts the orientation of these new neurons in the hippocampus.  This disruption interferes with building proper connections (Schafer et al, 2015).  Thus, children with deletions greater than 6 Mbase are likely have problems with “pattern separation,” the very subtle learning process that prevents new learning from interfering with old knowledge (Johnston et al, 2015).  The concept of pattern separation has arisen through complex mathematical learning models.

How can we take this information on CELSR1 and translate it into treatments?  There are several paths.  First, we would like someone to study a mouse missing one complete copy of Celsr1 (heterozygous knockout mouse) to make sure the effects seen in the current mice are not simply mutation effects (see Gene deletion versus mutation).  There is a scientist in Belgium, Fadel Tissir, who has a “null” mouse (no copies of the gene), but has not reported any studies with a heterozygous knockout mouse yet.  Second, we need to find out about outer hair cell loss and its potential impact on hearing.  Perhaps someday we can arrange for a medical histologist to examine the cochlea (hearing organ) from a 22q13 deletion syndrome organ donor. Third, we need genetic testing (sequencing is best) on all patients missing CELSR1 to identify cases where the remaining CELSR1 gene is mutated.  A mutation on the remaining CELSR1 gene could unmask recessive traits in a way that may be very informative.

Finally, if we really want to understand our children’s learning problems, we need to: 1) engage people involved in computational models of learning, and 2) study patients with interstitial deletions.  Interstitial deletions will allow us to study genes in better isolation.  These patients may be higher functioning, which is ideal for careful testing (see How to fix SHANK3). As the new studies start to bear fruit, we can then use the results to target our teaching methods.  Right now parents, teachers and our children are frustrated with how poorly our children learn. Imagine how much better it will be when we know how to maximize learning for each child based on their genetic report.  I dream of seeing the next generation of children with 22q13 deletion syndrome having all the benefits we never had for David.  Let’s take lesson planning into the 21st century!

arm22q13

Previous blogs


How to fix SHANK3

Have you ever met a child like mine?

How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

How to fix SHANK3

david-eating-cerial-bars
David snacking on some cereal bar bits
Aubree and Mickey rev 2
Human – Mouse Partnership

Anyone who has read most or all of my blog pages knows that my goal is to help parents, scientists and other members of the 22q13 deletion syndrome community understand how the genetic landscape of chromosome 22 must shape our thinking if we are going to realistically pursue treatments. If you have not read the earlier blogs, much of this one may seem foreign.  This blog is based heavily on prior ones.  Because of the overlap, I will omit scientific references and simply recommend reviewing prior posts for supporting evidence.


There has been a recent flurry of mouse model papers on the Shank3 gene. The number of model mice has passed one dozen.  People who work on Shank3 mice love to describe their rodents’ behaviors as mouse analogs to human behaviors.  When an unusual mouse behavior is “rescued” with a chemical compound, the implicit (sometimes explicit) suggestion is that mouse research is on a path to curing autism, “Phelan-McDermid syndrome” (PMS) and maybe even schizophrenia.  Some researchers like to define PMS as a disturbance of SHANK3, which guarantees that any SHANK3 fix will fix PMS, whether or not the child is any better.  I am not going to argue with this rosy, perhaps fanciful, view of current rodent research.  It helps patients’ families feel hopeful and keeps funding and publications flowing. These are good things that a more conservative interpretation of the data might never accomplish.

From a practical standpoint, however, we still need a strategy for fixing SHANK3 problems in humans.  We need a plan that has more to do with the human disorder than the rodent one, and more to do with  therapeutic benefit than a detectable statistical change. The plan needs to be based on what we know more than what we speculate.  The plan needs to be about the patients, not the scientists, funding agencies or feel-good charity organizations.

The first thing we don’t know is whether human SHANK3 mutation causes the same problems as SHANK3 deletion.  Numerous rodent studies speculate that the influence of Shank3 mutation is a “dosage effect”.  That is, the effect is simply due to how much SHANK3 protein is lost.  Yet, total removal of all SHANK3 protein from a mouse has less effect than many Shank3 gene mutations.  Among the many different Shank3 mutations studied in mice, the behavioral, molecular, electrophysiological and drug effects differ widely. This “diversity of phenotypes” is the hallmark of a mutation syndrome, not simply a dosage effect.  In other words, in rodents there is a Shank3 mutation syndrome that is different from Shank3 deletion.

What about humans?  Is SHANK3 mutation different from SHANK3 deletion?  Well, no one knows, because only one patient has ever been described in the published literature as having a complete SHANK3 deletion without also damaging or removing other well-established brain genes, and the published information on that patient is limited.  It should not be necessary to emphasize this, but it make no sense to talk about exquisitely, selectively removing exactly one gene in a mouse and comparing that to humans missing 20, 30 or 100 genes. Any study based on a mouse model that accidently knocked out 2 or 3 nearby genes would never get published.  It is disingenuous to insist on precision mouse gene editing and then make comparisons to patient populations that are nearly devoid of matching examples. It is inconvenient that we don’t have clean human examples, but we parents of 22q13 deletion syndrome children deal with a lot of inconveniences that we cannot wish away.  In that regard, we are not very sympathetic to wishful scientists.

So, let’s be clear on what we don’t know.  We don’t know if selective SHANK3 deletions are different from SHANK3 mutations in humans.  However, we do know that humans with different SHANK3 mutations can have very different presentations, including autism spectrum disorder (ASD), intellectual disability (ID), combined ASD with ID, and combined schizophrenia with ID. So, we know that the diversity of phenotypes associated with mouse Shank3 mutations parallels the diversity of human phenotypes.  This parallel gives us some, albeit weak, evidence that the effects of human SHANK3 mutations are not a simple a dosage effect.  We are still limited by the paucity of human cases to assess the real impact of a pure SHANK3 deletion.

Wishful thinking aside, let’s go with what the (limited) evidence says: human SHANK3 mutations (including deletions that disrupt the gene) probably have effects other than reducing the availability of SHANK3 protein.  Because mutation syndromes are not uncommon on chromosome 22 and elsewhere, there is ample precedence for understanding how mutations can disrupt normal function. The mouse (and human) Shank3 gene has 7 intragenic promoter regions and  an estimated 20 to 100 natural isoforms (variants of the protein produced). The SHANK3 protein is very similar to SHANK1 and SHANK2, with many molecular binding partners in common.  That is, the three shank proteins  all interact with essentially the same molecules in the neurons of the brain. Taking a reasonable speculative leap, mutation of SHANK3 gene can produce some or many SHANK3 fragments that wreck havoc with the assembly of the synapse. As an analogy, think about placing a bunch of defective nuts and bolts into the manufacturing process for a car or airplane. The production line is better off substituting different hardware (e.g., using SHANK1 or SHANK2) than installing parts with defective hardware (broken bits of SHANK3).   The somewhat unexpected conclusion is that we might be able to treat disorders of SHANK3 mutation by shutting down the SHANK3 genes partially, or altogether. This approach can be tested in mice.

If we are considering SHANK3 deletion as a treatment for SHANK3 mutation, then we better be prepared to treat SHANK3 deletion.  I believe recent results from the first Shank3 complete knockout mouse provides a path for understanding and treating human SHANK3 deletion.  The most abiding and measureable effect of complete Shank3 deletion in the mouse is failure to engage and benefit from an operant conditioning task (lever pressing for a reward).  This effect appears to be associated with abnormal ventral striatal function, which is consistent with many previous studies of the ventral striatum.  Failure to explore and learn would be indicative of ID in humans, so it is of great interest to understand the exact relationship between the learning deficits in humans with pure SHANK3 deletions and mice with pure (complete) Shank3 deletions.  Such an undertaking would require a very modern and somewhat novel strategy in the world of pre-clinical neuropsychiatric research.

The precise nature of the mouse learning deficit is not yet understood.  Learning is a complex process and many aspects are very subtle.  Even the reported rescue of learning in the Shank3 knockout mouse creates more questions than answers.  These questions go to the heart of how SHANK3 loss might contribute to intellectual disability in humans.  How can the details of learning deficits caused by SHANK3 deletion be dissected out?  Given the rarity of pure SHANK3 deletion, I propose that a single subject (or two) be invited as true participants in a scientific study of their learning abilities, and that the latest computational approaches (often used in animal research) be applied in a series of iterative testing to model and measure the learning deficits.

Current, state-of-the-art scientific learning studies are computationally based.  Learning tasks are designed to incorporate variables that can be directly tied to equations describing an underlying theoretical framework of the learning process.  Animal researchers are adept at designing learning tasks in ways that do not require verbal instruction.  They  are equally practiced at inferring the results without the need for verbal reports. Still, with the participation of a fluent verbal subject, researchers can work with the subject to help design tasks (games) that are interesting and engaging.  Rewards for mice are often in the form of sweetened concentrated milk droplets.  For healthy adults, money is commonly used as an incentive.  The SHANK3 deletion participant may prefer to see dancing fairies or a music video clip.

As these learning tasks  begin to characterize the nature of the deficit seen in the subject/participant, they are then re-designed for testing in animal models. Current rodent models can be used, but there is no reason the same tasks cannot be explored in nonhuman primates for fMRI and electrophysiological investigation. The technology of gene editing, common in mice, has reached farm animals and at least two species of nonhuman primates.   As these methods become more mainstream, complete SHANK3 deletion could be a practical research option, especially in old world monkeys, species that shares important common features with human cortical evolution.

The goal of this scientist/participant research partnership is to develop a sensitive cross-species measure of learning ability that parametrizes the impact of SHANK3 dosage.  Such a measure provides two invaluable assets to the development of treatments. First, animal models can be validated (or not) based on exquisite computational approaches that may be able to distinguish species differences from the influence of SHANK3 dosage.  Second, interventions, either learning-based or pharmaceutical, can be tested using measures sufficiently sensitive to reflect the identified nature of the deficit. What can this human research/animal research partnership hope to produce?  The first successes may be refinements to educational methodologies.  The learning models could point the way to improvements in teaching strategies.  Later, dare we hope, may be pharmaceutical interventions.

Wouldn’t it be splendid if parents could continue to hope, scientists could continue to get published, feel-good organizations could continue to raise money, and in the meanwhile, our kids could get better, too?

 

arm22q13

Previous blogs

Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

Have you ever met a child like mine?

Sometimes, David likes to be held.
Sometimes, David likes to be held.

Jannine Cody, the parent/scientist who studies 18q deletions, says that since every deletion is different, every child with a deletion is different.  At the PMS family conferences we met other children with 22q13 deletion syndrome who, at the time, had striking similarities with David.  These children had chromosome 22 deletions of various sizes, and similar children did not always seem to have the same size deletions.  We know now that genes are not distributed equally along 22q13, so children with small deletions can be quite different from each other, and children with large deletions can be quite similar (see Understanding deletion size).  We also know there are good scientific reasons to expect differences (see How can the same deletion have such different consequences?).  Some things are pretty obvious after a while.  The kids who could not walk or talk generally had larger deletions.  Those with larger deletions also had many more medical problems.  Obviously, more genes lost means more problems.  Regular readers of this blog have seen evidence of why it is very important to know which genes are missing (see How do I know which genes are missing?).

Some people feel that research on 22q13 genes should be done one gene at a time, starting with SHANK3.  I am not a big proponent of this approach, since it ignores a lot of research already done on ARSA, MAPK8IP2, CHKB, CPT1B,  PANX2, ALG12, BRD1, SULT4A1 and other genes known to cause disorders in humans, mice or both.  The one gene-at-a-time approach also slows research by making one gene sound much more important than others.  It seems to me if we spend 5 to 10 years on each gene, we are doomed to spending 500 to 1,000 years. If that sounds pretty absurd, well, it is.  Maybe it will only take 200 years to do it this way.  That still seems too long to me.  That is why I recommend the scientific program be managed by someone with a deep understanding of science leadership (see 22q13 deletion syndrome and science leadership).  The “SHANK3 or bust” research program has succeed in some ways.  Recently, after about a dozen mouse models of Shank3, there is a new mouse with the first complete deletion of the gene. All the other mice were various examples of gene mutation.  As we know, the effects of mutation (or removing part of the gene) can be very different from deletion (see Gene deletion versus mutation: sometimes missing a gene is better). This is critically important! The main reason for supporting Shank3 mouse research is the argument that most (not all) patients are missing the SHANK3 gene entirely.  Thus, it is SHANK3 deletions that make the research important to our families. (Note that mouse Shank3 mutation research has a very separate goal: understanding how mutations might contribute to general forms of autism.)

So, we now have a real Shank3 deletion mouse and everyone is very excited about it (Mouse Model of Autism Offers Insights to Human Patients, Potential Drug Targets).  Of course, be skeptical of what the university PR team says (see Mouse models).  Let’s take a look at this first-ever complete Shank3 knockout mouse. First off, the major finding is that this mouse is different from the many mutation mouse models.  No one should be surprised.  What is surprising is that you have to completely wipe out 100% of Shank3 to see a measurable difference between these mice and normal mice. Even more shocking is that these mice are walking around, playing with other mice, eating, talking mice talk (ultrasonic sounds) with no shank3 whatsoever in their bodies!  The mice missing 100% of Shank3 are different from other mice, but mice missing 50% are not different in any measurable way. Note that humans with 22q13 deletion syndrome are missing only one of the two genes and best evidence is that they have lost only about 25% of their shank3 protein (See this research paper).

So, is there something wrong with the mouse study?  Are mice just way different from humans, or is there another explanation?  Maybe it all makes sense.  Have you ever met a human missing all of SHANK3 and only SHANK3?  The complete knockout Shank3 mouse is best compared with a person like that, someone who is not missing any other genes and has no known mutations.  It is not good enough to have someone with a “small deletion”, since there is strong evidence that adjacent genes impact brain function.  This mouse models SHANK3 deletion.  I have met only one person who seems to fit this description.

Phelan McDermid syndrome is characterized by developmental delays, moderate to severe intellectual disability, little or no expressive language, and infant hypotonia (floppy baby syndrome).  Some people argue that the syndrome is also characterized by a high incidence of autism spectrum disorder, although some top scientists disagree.  The person I met was probably never a floppy baby, has practically normal speech, and that person has no evidence of autism.  Rather, the person I met has some problems with coordination, has a great difficulty learning and is socially a wonderful person to meet and engage with, perhaps to a fault.  Tragically, like all of our children, that person will never navigate the world well enough to live an independent life.

In summary, when I read the scientific paper on the complete Shank3 knockout mouse, what struck me was how many tests the complete, 100% knockout mouse passed without demonstrable evidence of a problem. Mice missing one copy are normal in almost every test.  Mice missing both copies are not “normal”,  but clearly, even these mice are nothing like my son.

How important is SHANK3?  It is impossible to make that judgement based on only one clinical case.  The person I met has lost all independence for that person’s entire life. That is very important.  Moreover, it is tragic.  But for 95% of families, 22q13 deletion syndrome comes with the full set of core features of 22q13 deletion syndrome.  David cannot tell me when he feels sick, where it hurts, or if he was mistreated in his group home. It took him 6 years to overcome his floppy baby syndrome enough to walk and three more years before he could eat by mouth.  His autism-like features interfere with social contact.

As of now, the most parsimonious explanation of what we know is that SHANK3, alone, does not produce the core features of 22q13 deletion syndrome.  It is a contributor in most, but not all, cases.

 

arm22q13

 

Previous blogs

How do I know which genes are missing?
Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

How do I know which genes are missing?

David March 5David decided to stand still so I could
take his picture.  Thanks David!

I often get asked to interpret a genetic report.  I am not a clinician of any sort. I never even had a genetics course.  But, there are certain skills one must pick up along the way to study which genes are missing in 22q13 deletion syndrome and what they do.  So, I have some idea how to read a report, just enough to accomplish my goals.

If you have a genetic report, here are some ways you, too, can figure out which genes are missing.  David only had a FISH test 15 years ago, so I don’t know how many genes he is missing.  You may be in much better shape. If you had an array or sequence done on your child, you should have enough information to find out which genes are missing.  Here is how.

Expert mode

The experts use the technical part of a genetic report to see what has been deleted. The technical part will often look something like this:
hg17  arr 22q13.33 (48,230,183-49,523,149) X1
This example is a simple terminal deletion of chromosome 22 (not a real case).  It says that part of chromosome 22 only has one copy (X1).  The nomenclature can get complicated if there are multiple genetic problems.  The nomenclature is outlined here:
http://www.radford.edu/~rsheehy/cytogenetics/Cytogenetic_Nomeclature.html

Once you know which base-pairs are missing (48,230,183-49,523,149) and which genome assembly was used to make the measurement (hg17), you can go to the UCSC Genome Browser and get gobs of information about the deletion.  The Genome Browser is complicated to use, but I use it often. 

Simplest

Sometimes the report provides a complete list of the missing genes.  “Complete” is relative to certain things.  For instance, most gene array studies cannot detect the presence or loss of the last gene on the chromosome, RABL2B.  This gene is too similar to RABL2A and no one thinks RABL2B is important enough to make a special effort to detect it. (I happen to disagree. See my blog Is 22q13 deletion syndrome a ciliopathy.) Otherwise, the gene list is useful.  If the only listed genes are SHANK3 and ARSA, the gene list is worthless.  It means the geneticist either did not want to look up, or share with you, the other genes that are missing.

End gene or deletion size

If the deletion is a terminal deletion, you can use the deletion size to look up the genes on my list (below).  If the report says something like, “from PLXNB2 to ACR” or “distal to” PLXNB2, then you can find PLXNB2 on the list and it becomes the marker for where the deletion starts. Terminal deletions start from the “end” gene and go up the list (down in gene number on my list).

Go to the Foundation’s web site?

If you had 18q deletion syndrome, there is a site that was created for parents to look up the genes that are missing and what those genes do.  No such site exists for 22q13.

Ask your geneticist

I have seen some very nice genetics reports with a complete list of genes deleted.  This is rare, but you might try asking for such a document.

The list

Here is a list of the genes that covers the last 15,000 KB (15 MB) of 22q13.  That is probably larger than the largest known terminal deletion.  The list comes with a few caveats.  First, deletions can be messy.  Sometimes lots of genes are gone, then part of the subsequent gene is gone.  People don’t count half a gene.  They usually add the partial gene to the gene count. Micro arrays (gene chips) sample the genes every so many kilobases (KB).  It is not a continuous readout of the DNA.  Thus, in most cases, you don’t know the exact position of the break.   DNA includes many things in addition to genes. It encodes things called microRNAs, and the DNA has essential gene promoter, inhibitor and enhancer regions within genes and between genes.  Thus, a gene list tells only part of the story.  Finally, I found an error in my list this past week, so let me know, but please don’t complain if this has more errors!  I will correct this page as I find errors.  However, I emphasize that this list comes without any warranty whatsoever.  I take no responsibility for its use.  It is part of a blog to educate parents.  It is not a tool for legal, medical or any other practice. Ok?
[updated/corrected 6 March 2016]
[updated/corrected 12 March 2016]
[updated/corrected 17 June 2016]
[updated/corrected 5 December 2016]
Table now shows the smallest distance to the gene. For example, a terminal deletion of size 196.0 Kbase will delete all the genes before ARSA and damage part of ARSA.

#       Gene       Deletion size (Kbase) 
1       RABL2B        34.81 
2       ACR           78.11 
3       SHANK3        85.17 
4       ARSA         195.14 
5       MAPK8IP2     206.92 
6       CHKB         235.47 
7       CPT1B        240.05 
8       SYCE3        255.56 
9       KLHDC7B      267.45 
10      ODF3B        286.65 
11      TYMP         288.47 
12      SCO2         292.86 
13      NCAPH2       295.00 
14      LMF2         310.78 
15      MIOX         328.43 
16      ADM2         332.03 
17      SBF1         343.44 
18      PPP6R2       373.38 
19      DENND6B      491.41 
20      PLXNB2       539.63 
21      MAPK11       548.08 
22      MAPK12       557.16 
23      HDAC10       567.21 
24      TUBGCP6      573.90 
25      SELO         600.85 
26      TRABD        618.90 
27      PANX2        638.18 
28      MOV10L1      656.85 
29      MLC1         733.11 
30      TTLL8        763.84 
31      IL17REL      809.78 
32      PIM3         854.39 
33      CRELD2       895.76 
34      ALG12        900.01 
35      ZBED4        928.39 
36      BRD1         995.26 
37      C22orf34     1,160.96 
38      FAM19A5      2,067.65 
39      TBC1D22A     3,642.77 
40      CERK         4,080.21 
41      GRAMD4       4,180.53 
42      CELSR1       4,281.30 
43      TRMU         4,484.77 
44      GTSE1        4,487.66 
45      TTC38        4,543.18 
46      PKDREJ       4,555.11 
47      CDPF1        4,570.18 
48      PPARA        4,620.06 
49      PRR34        4,764.32 
50      WNT7B        4,841.34 
51      ATXN10       4,973.16 
52      FBLN1        5,287.14 
53      RIBC2        5,385.97 
54      SMC1B        5,404.90 
55      FAM118A      5,508.30 
56      UPK3A        5,522.59 
57      KIAA0930     5,577.70 
58      NUP50        5,630.45 
59      PHF21B       5,809.48 
60      ARHGAP8      5,955.68 
61      PRR5         6,080.79 
62      LDOC1L       6,320.17 
63      KIAA1644     6,505.62
64      PARVG        6,610.00 
65      PARVB        6,649.55 
66      SAMM50       6,821.94 
67      PNPLA3       6,870.90 
68      PNPLA5       6,926.46 
69      SULT4A1      6,955.97 
70      EFCAB6       7,248.33 
71      MPPED1       7,310.62 
72      SCUBE1       7,475.08 
73      TTLL12       7,631.34 
74      TSPO         7,655.23 
75      MCAT         7,675.07 
76      BIK          7,688.76 
77      TTLL1        7,729.13 
78      PACSIN2      7,942.26 
79      ARFGAP3      7,961.07 
80      A4GALT       8,123.48 
81      ATP5L2       8,177.87 
82      CYB5R3       8,173.96 
83      RNU12        8,203.08 
84      POLDIP3      8,203.60 
85      SERHL2       8,260.06 
86      RRP7A        8,298.67 
87      SERHL        8,305.91 
88      NFAM1        8,386.07 
89      TCF20        8,603.03 
90      CYP2D6       8,688.56 
91      NDUFA6       8,727.69 
92      SMDT1        8,735.12 
93      FAM109B      8,739.03 
94      NAGA         8,747.64 
95      WBP2NL       8,785.70 
96      SEPT3        8,828.88 
97      CENPM        8,871.30 
98      TNFRSF13C    8,891.65 
99      SHISA8       8,903.80 
100     SREBF2       8,911.16 
101     CCDC134      8,992.58 
102     MEI1         9,019.01 
103     C22orf46     9,124.62 
104     NHP2L1       9,129.56 
105     XRCC6        9,154.43 
106     DESI1        9,197.37 
107     PMM1         9,228.58 
108     CSDC2        9,241.80 
109     POLR3H       9,273.98 
110     ACO2         9,289.48 
111     PHF5A        9,349.74 
112     TOB2         9,371.45 
113     TEF          9,419.14 
114     ZC3H7B       9,458.32 
115     RANGAP1      9,532.50 
116     CHADL        9,578.85 
117     L3MBTL2      9,587.20 
118     EP300        9,638.39 
119     RBX1         9,854.06 
120     DNAJB7       9,956.34 
121     XPNPEP3      9,948.13 
122     ST13         9,961.45 
123     SLC25A17     9,999.14  
124     MCHR1        10,135.65 
125     MKL1         10,181.78 
126     SGSM3        10,412.25 
127     ADSL         10,457.16 
128     TNRC6B       10,662.29 
129     FAM83F       10,774.94 
130     GRAP2        10,844.75 
131     ENTHD1       10,924.68 
132     CACNA1I      11,133.94 
133     RPS19BP1     11,285.61 
134     ATF4         11,295.79 
135     MIEF1        11,314.17 
136     MGAT3        11,326.27 
137     TAB1         11,386.59 
138     SYNGR1       11,440.08 
139     SNORD43      11,499.36 
140     RPL3         11,499.85 
141     PDGFB        11,573.72 
142     CBX7         11,668.64 
143     APOBEC3H     11,715.91 
144     APOBEC3G     11,731.05 
145     APOBEC3F     11,773.28 
146     APOBEC3D     11,786.15 
147     APOBEC3C     11,798.12 
148     APOBEC3B     11,825.92 
149     APOBEC3A     11,865.05 
150     CBX6         11,946.15 
151     NPTXR        11,974.49 
152     DNAL4        12,024.30 
153     SUN2         12,062.94 
154     GTPBP1       12,084.88 
155     JOSD1        12,117.80 
156     TOMM22       12,133.05 
157     CBY1         12,150.00 
158     FAM227A      12,161.84 
159     DMC1         12,250.06 
160     DDX17        12,312.13 
161     KDELR3       12,335.02 
162     KCNJ4        12,363.27 
163     CSNK1E       12,500.38 
164     TMEM184B     12,545.43 
165     MAFF         12,614.42 
166     PLA2G6       12,636.67 
167     BAIAP2L2     12,707.80 
168     SLC16A8      12,735.33 
169     PICK1        12,759.16 
170     POLR2F       12,791.78 
171     SOX10        12,835.05 
172     POLR2F       12,846.17 
173     C22orf23     12,864.80 
174     MICALL1      12,896.18 
175     EIF3L        12,929.06 
176     ANKRD54      12,974.04 
177     GALR3        12,992.97 
178     GCAT         13,001.29 
179     H1F0         13,011.03 
180     TRIOBP       13,041.91 
181     NOL12        13,124.99 
182     LGALS1       13,138.66 
183     PDXP         13,151.53 
184     SH3BP1       13,162.43 
185     GGA1         13,184.90 
186     LGALS2       13,238.39 
187     CDC42EP1     13,249.06 
188     CARD10       13,321.69 
189     MFNG         13,332.08 
190     ELFN2        13,391.00 
191     CYTH4        13,520.79 
192     RAC2         13,574.20
193     SSTR3        13,606.15

Check out my earlier blogs (below) to learn how many of your friends are missing a similar number of genes and which genes might be important.  If you find this information valuable, please leave me a positive comment, or repost the blog elsewhere (e.g., Facebook).  Many thanks to each parent who has shared his/her child’s information and shared their own very personal stories. Your contributions and feedback helps me feel that I am not alone in the quest to make the world a better place for our kids.

arm22q13

Previous blogs

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Mouse models

DRW51015. Model of SR-71A Blackbird by Dragon Models ( /www.dragon-models.com.cn )
DRW51015. Model of SR-71A Blackbird by Dragon Models ( http://www.dragon-models.com.cn )

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.

 

arm22q13

 

Previous posts:

Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction