Which PMS genes are most associated with Autism?

Figure 3
Genes disrupted in autism and schizophrenia.  Modified from Gandal 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 (Gandal 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.



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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