Home > Science > Shank synaptic genes in autism: Human genetics to mouse models and therapeutics

Shank synaptic genes in autism: Human genetics to mouse models and therapeutics

This is a guest post by by Mehreen Kouser, a Dennis Weatherstone Fellow, and Ph.D. Candidate working with Dr. Craig Powell at the UT Southwestern.

This year IMFAR hosted a Scientific Panel titled “Shank synaptic genes in autism: Human genetics to mouse models and therapeutics” organized and chaired by Dr. Craig Powell. This panel consisted of four presentations starting with the unequivocal role of Shank3 in autism and ending with potential treatment strategies in genetically mutated mouse models of Shank3.

Over the past few years , Shank3 has emerged as the new “it” gene for autism. Current estimates suggest that Shank3 errors account for 0.5-2 % of autism diagnoses making it a major genetic cause of  autism. Several recent human studies have implicated mutations/deletions/duplications in the Shank family of proteins, especially Shank3, to be involved in ASD and 22q13 Deletion Syndrome.  Shank3 is a scaffolding protein that is involved in synapse architecture. Mutations in Shank3 are known to affect synaptic connections between neurons in similar ways to other autism-relevant genes such as neuroligin and neurexin. Thus understanding the role of Shank3 in autism is critical.

The first presenter at this panel was Dr. Catalina Betancur from INSERM in France. Dr. Betancur was a major player in the discovery of Shank3’s relevance to autism.  She carefully detailed all known human mutations, deletions, and duplications published since the first paper on Shank3 mutations in idiopathic autism was published in 2007.She also outlined the case for Shank3 as a major causative gene in the symptoms of the 22q13 chromosomal deletion syndrome known as Phelan-McDermid Syndrome.   In addition, Dr. Betancur detailed the work of her laboratory and others implicating Shank2, another member of the Shank gene family, in autism.

Dr. Joseph Buxbaum from Mount Sinai School of Medicine in New York was the next presenter. His laboratory was the first to publish a genetic mouse model of Shank3 successfully Shank3.  Their Shank3 mutant mouse closely mimics autism-associated mutations in this area of the Shank3 gene.  His work focused on the heterozygous mutation of Shank3 gene as this is the state of autism patients with Shank3 mutations. Characterization of this mouse model, clearly suggests that Shank3 plays an important role in synapse architecture, function, and plasticity. Among the most intriguing findings in his presentation was his ability to reverse the manifestations of Shank3 mutation in brain slices treated with Insulin-like Growth Factor-1 (IGF-1). This gives us the much needed hope that Shank3 mutation models of autism will lead to identification of novel therapeutic targets that can be validated in these models.

Next, Dr. Yong-hui Jiang from Duke University in North Carolina presented his work on a genetic mouse model very similar to that of Dr. Buxbaum’s group, but his focus was the homozygous mutation of Shank3 mutating both copies of the gene. He noted that the Shank3 gene is more complex than originally thought, with potentially having as many as six variants or isoforms. His careful analysis of this mutant model clarified that only a portion of Shank3 isoforms are affected by this genetic strategy.  He identified abnormalities in synaptic connection  morphology in his model.  Moreover, his lab characterized this mouse model extensively on autism related behaviors and found them to be impaired in the social behaviors, repetitive behaviors, communication, motor coordination and learning and memory. These results demonstrate that human diseases can be successfully modeled in mice. The hope is that if we can reverse them in mice, treatments for humans are not far away.

Dr. Joao Peca from Guoping Feng’s lab at MIT in Massachusetts concluded the session by presenting a completely different Shank3 mutation in mice.  He began his presentation by telling us about another synaptic gene called SAPAP3 and showing us its involvement in a repetitive grooming behavior in mice. He showed that SAPAP3 knockout mice continuously groom themselves and that this behavior can be reversed by putting this gene back into the striatum of mice later in life. He also showed that Shank3 is a strong binding partner of SAPAP3 and their Shank3 mutant mice have the same increase in repetitive grooming behaviors.   Like the other Shank3 mutations, this mutant does not affect all forms of Shank3, but may mimic a different human mutation.

This panel set the stage for future advances in the area of Shank3 and autism.  Only 4 years after the initial study implicating Shank3 in autism, we now have at least 3 different animal models and 4 publications on these models.  Although, we may face grave challenges in sorting through the heterogeneity of mutations, deletions, and duplications and their different consequences, these presenters clearly demonstrate that this strategy will lead to identification of potential therapeutic targets that can be readily tested in animal models.

  1. Katie Wright
    May 25, 2011 at 12:59 pm

    This Shank 3 research is grossly overfunded and overpromised. This gene affect 2-5% of people w/ ASD. There is absolutely no evidence that this research would benefit the other 95% of children suffering with this disorder. The presentation of autism in those w/ chromosomal abnormalities and those without is wholly different. We do not have the money nor the time to indulge in this type of research when so much more pertinent environmental and biomedical research goes unfunded.

    • Andy Mitz
      May 26, 2011 at 12:20 am


      This Shank3 research is very promising. It would be wonderful if we could find out exactly what causes and how to treat 2-5% of those with Autism, considering that we can now “treat” 0.0% of people with autism at the root cause. There are 100 identified genes that somehow contribute to autism. As we understand the connection to each genetic cause, we understand more and more about what autism is and why it occurs. It is a long road. Shank3 is just the first step. I remember when cancer was the same: mysterious, untreatable and struck fear into the heart of anyone with a cancer diagnosis. Every type of cancer is different from every other, not unlike the heterogeneous nature of autism. The first cancers studied were not necessarily the most common. Science often studies what can be understood first on the road to understanding the more difficult. Please don’t be so negative. Don’t spread negativity. Hope is important. Shank3 research brings important hope to everyone involved in autism. Of course, this is not going to bring anything like a cure tomorrow. It is the study of one tiny subpopulation of people with autism, but it is a very important and hopeful start into the deep mystery of autism that we will one day conquer.


  2. Katie Wright
    May 26, 2011 at 11:47 am

    I hear what you are saying Andy and appreciate your point of view.
    But I live w/ a severely ASD child who complex medical problems – If we research and
    treat these basic problems now we can make a tremendous impact on autistic kids living now. Right now too many parents cobble together treatments interventions from the internet and parent mentors. For yrs I have been running ivig, glutatione and TSO trials in my home because it is that or nothing. It is exceedingly hard for parents like me to see the value in Skank 3 research when clinical- interventions are such a low priority at these research institutions.

  3. Liz S
    May 26, 2011 at 11:24 pm

    I thought at IMFAR there was discussion about research completed out of Duke which showed lack/decreased expression of shank3 protien in brain tissue of those with idiopathic autism. if that is the case then shank3 research helps those with autism with a known shank3 abnormality but it may also translate to the general autism population.

  4. Geraldine Bliss
    May 27, 2011 at 11:58 am

    Thank you, Mehreen, for your summary of the Shank session at IMFAR. I attended the session too. As a lay person, I was inspired by what is being learned about the molecular bases of autism and the promising work being done by scientists studying the Shank complex.

    Katie, I share your frustration with the lack of guidelines for the medical management of ASD. My own frustration with managing my son’s complex medical issues is exactly what got me interested in the basic science of autism. I’m tired of trial and error with diets, supplements, and medications. It is time for us to have effective medical interventions that are based on a foundation of knowledge of the molecular bases of autism.

    I disagree with you about Shank3 research benefiting only a small percentage of patients with autism. Did you know that researchers looking at human autism brain tissue samples have found reduced levels of Shank3 and other autism-related proteins even when there was no change in the DNA sequence? This means there are probably a lot of people with ASD who have the same synaptic problems we see in patients who have been diagnosed with chromosomal abnormalities, but they will never find out through a blood test. We don’t know what triggers these expression problems. Doesn’t it seem like an important question that deserves increased funding? In the meanwhile, the handful of labs that are involved in Shank3 research are making important contributions that cast a much broader light on synaptic structure and function.

  5. Pam Wagner
    May 27, 2011 at 12:22 pm

    I have always thought that there was a strong genetic factor for ASD. Since my father’s family have live on an island since the 1600’s and there is a high rate of ASD within it I have always believed that there are many strands to follow in order to identify and treat or find better means to education our children. I am an identical twin who has a young adult with ASD, I have a son with ASD, a cousin with ASD as well as others who have been described as having ASD tendencies prior to the Disorder had a name. Everything that we learn will help us and future generations.I wonder if any program would want to study my family? It is not often when you have identical twins …

    • Zim Le
      May 28, 2011 at 11:29 pm

      Pam, absolutely. Not only you are in the rare group of identical twins with ASD or having family members with ASD, but your paternal genetic history and relatively geographical isolation may offer unique opportunities for study. It’s obvious from many posts herein that the writers are investigators in the ASD or closely-related fields. They’d sooner or later notice your post. But, to speed things up, I would write to Autism Speak’s Chief Scientist if I were you. Thank you for sharing.

      • Pam Wagner
        May 29, 2011 at 11:55 am

        Zim Le, I really appreciate the affirmation of what I have always believed. My sister and I have always felt that if anyone would to use us in a study we would be willing. Do you know how I can reach Autism Speak’s Chief Scientist? Thank you so much for responding.

  1. June 13, 2011 at 5:45 am
  2. June 13, 2011 at 4:59 pm

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