Which PMS genes are most associated with Autism?

Figure 3
Genes disrupted in autism and schizophrenia.  Modified from Gandel et al. 2018 Science.  doi:10.1126/science.aad6469.

The previous blog looked at the relationship between SHANK3 and autism risk (Does SHANK3 cause autism?). Today’s blog looks at another new study.  This study is an analysis of which genes are dysregulated (“out of whack”) in major psychiatric disorders, including autism and schizophrenia (Gandel et al. 2018 Science. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap).  In the previous blog we learned that people generally have slightly different versions (variants) of each gene.  An unlucky person may have hundreds to thousands of gene variants that, added up, conspire to create a high risk of autism.  Thus, there are a lot of different combinations of genes that can lead to autism.

What the new study shows is, regardless how a person gets autism or schizophrenia, the same networks of genes become dysregulated.  Let’s first discuss what gene regulation means.  DNA is like a well-stocked bakery.  A good cook can prepare many different kinds of breads or desserts by choosing how much of each ingredient to use, and when.  Just about every cell in the body has the same DNA.  What makes one part of the body different from another is how much, and when, each gene is used. DNA cooking is called gene regulation.  In autism and schizophrenia, the proportions of ingredients have gone awry.

The green diagram at the top of this blog maps the results of the new study.  The researchers found certain critical “modules” (functional groups) of genes that are dysregulated in the brains of individuals with these two disorders.  Once, again, these genes are dysregulated regardless of how one acquires autism or schizophrenia.   The map identifies the 20 most dysregulated genes in each module (140 total) and how they interact in the brain.

What does this diagram tell us?  It says some things we already knew.  Autism (and schizophrenia) cause problems in neurons, the brain cells responsible for sensation, thinking and action.  Less obvious, autism seems to be related to two other cell types, astrocytes and microglia.  Astrocytes nourish neurons.  Microglia, which also come in contact with neurons, are known to regulate the formation and removal of synapses.  There are other important cell types, as well.

What is the news for PMS?  We learn that two PMS genes are core genes of the dysregulated neuron networks. I have circled these genes in RED.  There are about 20,000 genes in the human genome.  The paper identifies the top 140 dysregulated genes. Obviously, they are quite important for psychiatric disorders.  The two PMS genes are MAPK8IP2 and SULT4A1.  Not surprisingly, MAPK8IP2 and SULT4A1 have already been identified as two of the 18 most important genes of PMS (see Which PMS genes are most important?).

Which individuals with PMS are missing these genes?  Nearly all (over 95%) of people with PMS are missing MAPK8IP2.  About 30% of people with PMS are missing both MAPK8IP2 and SULT4A1.  If your child has a typical (terminal) deletion, you can look up which important PMS genes are missing in this blog:  Which PMS genes are most important?

At this point, it seems pretty likely that deletions of 22q13.3 do more than raise the risk of autism.  Deletions can directly impact MAPK8IP2 and SULT4A1, two core genes dysregulated in autism, schizophrenia and other neuropsychiatric disorders.  Perhaps the good news is that people who study autism and schizophrenia have a new impetus to study MAPK8IP2 and SULT4A1.  It is up to PMS parents to lobby, cajole and otherwise let everyone know that studying these genes is very important to us.

 

arm22q13

Previous blogs

Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
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 modelsScience 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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We need to study interstitial deletions to cure PMS

David Jan 2018
David has a terminal deletion, but he will benefit from studies of interstitial deletions.

Two very recent studies of Phelan McDermid syndrome (PMS) drew exactly the same conclusion: We need to recruit and study more PMS patients with interstitial deletions if we are going to understand the syndrome (see references 1 and 2, below).  This blog explains why that is a critical need.  In some ways, this blog is an update to an earlier blog (Why don’t we have better drugs for 22q13 deletion syndrome?).

PMS can be broken down into a few obvious classes.  The original disorder, 22q13.3 deletion syndrome, has terminal deletions and interstitial deletions.  Later, SHANK3 variants (often called “mutations”) were added.  As I have discussed before (Gene deletion versus mutation: sometimes missing a gene is better), mutations are a mixed bag. Some mutations produce symptoms like 22q13.3 deletion syndrome, but other mutations produce other disorders (like ASD or Aspergers), or no disorder at all.

The overwhelming majority of 22q13.3 deletion syndrome / PMS cases are terminal deletions.  The smallest terminal deletions include the genes SHANK3, ARSA and RABL2B.  Of these, SHANK3 was identified as the most important gene for small deletions.  SHANK3 is not the only important gene (see Which PMS genes are most important?).  Early on, researchers were aware that interstitial deletions have the features of PMS (Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development).  Like other deletion syndromes (e.g., 16p11.2 deletion syndrome ), no one gene deletion explains all the cases of PMS.

PMS research started out with SHANK3, but somehow it got stuck there.  Being stuck has led to some serious deficiencies in our understanding of PMS.  First, very little is being done for the future of children with interstitial deletions.  Their SHANK3 gene is intact, so SHANK3 research does them no good.  Second, drug studies that use PMS patients to study SHANK3 are likely to fail without accounting for the important genes in each PMS patient.  This was discussed in the recent paper on PMS genes (reference 2). PMS patients have such a mix of deleted genes that the benefits of a drug for SHANK3 loss might not be detectable.  Third, certain serious problems seen in PMS are unlikely a result of SHANK3.  These issues, like poor thermoregulation (body temperature control), lymphedema, cerebellar malformation, mitochondrial problems, and certain developmental problems, impact a large proportion of children with PMS.  Every year children and adults with PMS die. We need to know which genes are associated with lethality. These issues will remain serious problems for people with PMS as long as SHANK3 remains the narrow focus of PMS research.  Even our understanding of SHANK3, itself, is incomplete without a much better understanding of the other important genes of PMS.  

The best way to understand the many genes of PMS is to study people with interstitial deletions.  They are the only PMS patients where we can safely say that SHANK3 deletion does not play a role. My last two blogs show that we actually know a lot about PMS genes that are most likely to cause problems.  However, we need to know much more about how each of these genes affect people.  That requires people with different size interstitial deletions.

There was one research study of people with interstitial deletions published in 2014 (Disciglio et al.).  It covered 12 patients.  Since that paper, there has been only one additional (single) case study  of an interstitial deletion.  By comparison, PubMed shows 164 papers with SHANK3 in the title.  Most PMS families are probably not aware that the current major studies of PMS specifically exclude interstitial patientsNatural History of Phelan McDermid Syndrome and the Electrophysiological Biomarkers of Phelan-McDermid Syndrome.  Some of the sites in these multisite studies have not excluded participants with interstitial deletions, recognizing the scientific importance of these cases.  Scientifically, excluding interstitial deletion patients makes no sense.  We should be seeking them out, recruiting them.  As a parent, excluding interstitial deletions seems unfair to both those families, and to the rest of us.  We need to get unstuck. We need the best science possible to help our children.

 

arm22q13

References

  1. A framework to identify contributing genes in patients with Phelan-McDermid syndrome. NPJ Genom Med 2017
  2. Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Gen 2018

 

Previous blogs

What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
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 modelsScience 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

 

Why don’t we have better drugs for 22q13 deletion syndrome?

david-19-feb-2017-cropped2

David does not talk, although I am certain he would like to.  He has poor hand control.  He can just barely manage a spoon or glass of water with great effort.  Although he walks a lot, he is always at risk of falling.  There are so many things that are difficult for David.  It would be nice if we had a medication to make his life easier.

After years of drug testing on children with 22q13 deletion syndrome we are probably no closer to a treatment now than when it started.  This problem is not unique to 22q13 deletion syndrome; it is true for many, if not most neuropsychiatric disorders (see: Hope for autism treatment dims as more drug trials fail).  Recently, Rachel Zamzow wrote a very readable review about why autism clinical trials have failed (Why don’t we have better drugs for autism?).   Her review is in Spectrum, the on-line magazine affiliated with the Simons Foundation Autism Research Initiative (SFARI). Rachel identifies three problems that plague clinical trials: 1) bad design, 2) wrong measures and 3) too broad a range of participants.  While problems 1 and 2 are important, problem 3 is a major stumbling block for 22q13 deletion syndrome that I would like to address.

Clinical trials for 22q13 deletion syndrome are intended to treat defects or loss of SHANK3 (Kolevzon et al., 2014).  The problem with finding a treatment for SHANK3 is just as Rachel – and many others – have described.  If the subjects you are testing are too diverse, you will never see a clear impact of the drug you are testing.  The subjects recruited for these studies have either SHANK3 mutations or have 22q13 deletion syndrome with terminal deletions of different sizes.  This group is more diverse than many, perhaps all, of the other autism-related clinical studies that have failed.  Going on past experience in the field, this clinical group will not provide useable results. Here are the reasons why.

SHANK3 mutations are complicated

Early on, there was hopeful enthusiasm about hunting for a cure for people with 22q13 deletion syndrome.  At that time, SHANK3 mutations were lumped together with chromosomal deletions.  Importantly, SHANK3 mutations were thought of as simply a loss of SHANK3 function.  As it turns out, SHANK3 mutations are tremendously complicated. Different SHANK3 mutations can have very different effects on the gene, on the proteins it produces, on the neural development of the brain, and on the impact it has on both people and experimental animals.   The most recent and most thorough review of Shank proteins (Monteiro and Feng, 2017) says it clearly: “Indeed, the idea that isoform-specific disruptions [different mutations] will result in different phenotypic consequences (and even result in different disorders) has recently gained momentum.”  I can say with some pride that the momentum includes my June 2016 blog How to fix SHANK3, which makes that very same point.  You cannot lump together people with different SHANK3 mutations and expect to get a single clear result.

Too few patients have the same SHANK3 mutation

To date, no one has been able to find enough people with the same SHANK3 mutation to do a drug study.  You can find SHANK3 mutations in large autism databases, but these are not like a registry where you can call the patient up and ask them to participate.  There is no doubt that medical researchers would pull together a SHANK3 drug study population, if they could.  Autism is thought to be a polygenic disorder (like schizophrenia). Thus, we expect that many individuals from autism databases will also have mutations of multiple autism-related genes, not just SHANK3.  Finding a large enough group of people with one (or two) SHANK3 mutations to study drugs will probably never happen.

Individuals with 22q13 deletions are too diverse

Another approach might be to use 22q13 deletion syndrome patients with terminal deletions that remove SHANK3 altogether.  Every one of these patients would have exactly the same SHANK3 loss.  Further, there is a registry for 22q13 deletion syndrome patients that might help with recruitment (PMSIR).  While this seems appealing, it has its own flaw.  Just as the SHANK3 mutation population is likely to have other autism and intellectual disability genes complicating the picture, chromosome 22 is full of genes that likely contribute to autism, intellectual disability, hypotonia and other phenotypic traits associated with SHANK3.  Anyone who has read my other blogs has seen numerous examples of those genes (see Mouse models and How do we know which genes are important?).  Because of the densely packed genes near SHANK3 (see Understanding deletion size), it is unlikely that a big enough group of people with 22q13 deletion syndrome can be found with deletions that don’t involve other critical genes on 22q13.

Solutions

In her article, Rachel Zamzow discusses the N-of-1 Trials approach. We parents do this all the time.  We experiment with different medicines on our one child. N-of-1 design simply has the clinical researcher follow the child during the test.  I’m not a big fan of N-of-1.  I prefer a mixed experimental approach where research animal testing is done in tandem with human testing (see Have you ever met a child like mine?).

In their detailed review of Shank proteins and autism, Monteiro and Feng recommended that “..careful genotype-phenotype patient stratification is required before individual testing of specific pharmacological agents.”   That is, don’t test drugs until you understand the impact of the genes that have been lost.  If you have been reading my blogs, that should sound very familiar.

Two things must change before we can expect drug testing to bring meaningful results.  First, we need to organize Phelan McDermid syndrome, SHANK3 mutation syndrome(s), and chromosome 22q13 deletion syndrome into a meaningful “genotype-phenotype patient stratification”.  That is, we need to define different types and subtypes of the syndrome that was once called 22q13 deletion syndrome.   I proposed running an interactive session with parents and researchers in 2012, and for the session I put together a Power Point presentation called: “Defining PMS across Genotypes Phenotypes and Molecular Pathology.”  I was asked not to present my ideas.  Perhaps I will be given a chance, someday.

Second,  we must spend the time to characterize the genes that are near SHANK3 on chromosome 22 and understand (in experimental animals) how they might contribute to 22q13 deletion syndrome.  We need to study people with interstitial deletions, so we can isolate the effects of these genes. Efforts to explore the contributions of 22q13 genes has been lacking, yet they are a major impediment to the search for effective drug treatments.

22q13 deletion syndrome has left David completely dependent upon others for his day-to-day living. Both David and I have come to accept that.  What we cannot do for David is know where it hurts when he is sick or injured. If I had one wish for a new medicine, that medication would let David point to where it hurts. That medicine, or any useful medication, is not going to happen until someone takes the needed steps to remove the impediments that interfere with productive drug testing. It is clear where we need to go.  The question becomes, who will take us there?

arm22q13

 

Previous blogs

What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
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