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

 

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2 thoughts on “How to fix SHANK3

  1. I continue to appreciate your constant attention to the details of current studies, and to work on changes to methadology that sound worthy of consideration. Are you able to communicate these ideas to a more learned audience where hopefully they could affect greater influence? Again thanks for what you do!! Joel

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    • Thank you, Joel. I am working on many fronts. This blog speaks from the heart of a parent and is aimed at education. It is amazing to me how few people understand the full gamut of 22q13 deletion syndrome. Parents, scientists, and “community leaders” all seem to have large blind spots. We can all use some education. Each time I write a blog I learn a lot researching it, writing it and after soliciting feedback. I have several blog drafts that I abandon after discovering my own indefensible misconceptions. The entire series of blogs tries to bring everyone up to the same place in understanding. If people read through them with an effort to understand, we could all sit down have have a serious discourse on how to achieve meaningful benefits for our children. Unfortunately, truly productive conversations have not happened. Too many people are invested in their own approach for one reason or another.

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