Shank3

SHANK3 Duplication Leads to Hyperactivity in Mice

Source: 
Simons Foundation Autism Research Institute
Date Published: 
December 17, 2013
Abstract: 

Mice with a duplication of SHANK3, a gene with strong links to autism, are hyperactive and manic, reports a study published in Nature.The mice produce about 50 percent more SHANK3 protein than their genetically typical counterparts, the scientists found, much like people with an extra copy of the gene do. The mice also show signs of hyperactivity. The team observed on further testing that the SHANK3 mice show behaviors typically seen in people going through manic episodes. The mice are easier to startle, eat more, have disrupted sleeping patterns and show heightened sensitivity to amphetamine. The mice also have spontaneous seizures.

ASF Grantee Publishes Paper in Nature that Brings Insight to Study of Phelan-McDermid Syndrome and Autism

Source: 
Nature
Date Published: 
October 16, 2013
Year Published: 
2013
Abstract: 

A new study brings important insights about the cellular and molecular mechanisms involved in the loss and gain of synaptic function in human neurons from patients with Phelan-McDermid syndrome and autism. It also provides encouragement that neurons derived from induced pluripotent stem cells of patients will be useful in understanding and developing treatments for neurodevelopmental and psychiatric disorders.

By Dr. Oleksandr Shcheglovitov
 
22q13.3 deletion syndrome (also known as Phelan-McDermid syndrome) is a genetic neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and autism. The syndrome is caused by the heterozygous microdeletions in the terminal region of chromosome 22. Although, a candidate gene responsible for the neurological abnormalities in patients has been suggested (SHANK3, which encodes a scaffolding protein of excitatory synapses), cellular and molecular defects associated with this syndrome were unknown. In the study published in Nature today, researchers from Stanford University reported that human neurons derived from induced pluripotent stem cells of patients with Phelan-McDermid syndrome and autism have deficits in excitatory synaptic transmission due to reduced number of excitatory synapses. The authors demonstrated that SHANK3 is primarily responsible for these deficits, as neurons from patients had reduced SHANK3 expression and increasing the levels of SHANK3 expression rescued synaptic deficits in patient cells.
 
The authors also tested several drugs for their ability to increase the number of excitatory synapses in neurons derived from patients and found that prolonged treatment with Insulin Growth Factor 1 (IGF1) completely restores excitatory synaptic transmission in patient cells. Interestingly, IGF1 produced its action by increasing the number of different type of excitatory synapses that express scaffolding protein PSD95 and lack SHANK3 expression.
 
In summary, this study brings important insights about the cellular and molecular mechanisms involved in the loss and gain of synaptic function in human neurons from patients with Phelan-McDermid syndrome and autism. It also provides encouragement that neurons derived from induced pluripotent stem cells of patients will be useful in understanding and developing treatments for neurodevelopmental and psychiatric disorders.

The Autism Science Foundation and the NIH Fund Study of Promising Treatment for Autism Subtypes

Source: 
Newswise
Date Published: 
August 26, 2013
Abstract: 

Scientists at the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai have received grants from the National Institutes of Health and the Autism Science Foundation to study Insulin-Like Growth Factor-1 (IGF-1), a promising treatment for subtypes of autism. Clinical Director at the Seaver Autism Center, Dr. Alex Kolevzon, says, "IGF-1 has the potential to be effective in treating Phelan-McDermid Syndrome and other types of autism spectrum disorder. We are very pleased that the NIH and the Autism Science Foundation have recognized this by providing us funding to continue our work in bringing this medication to our patients.”

Hear more from Dr. Alex Kolevzon on the ASF YouTube channel here.

Majority of Individuals with SHANK3 Gene Problems Have Both Autism and Severe Intellectual Disability

Source: 
Molecular Autism
Date Published: 
June 11, 2013
Abstract: 

Prospective study of 22q13 deletion syndrome and SHANK3 deficiency shows that the majority of individuals with a SHANK3 deficiency show both signs of autism and severe intellectual disability.

First Prospective Study on the Effect of Shank3 Deficiency on Phelan-McDermid Syndrome

Source: 
Molecular Autism
Date Published: 
June 11, 2013
Abstract: 

ASF Scientific Advisory Board Member, Joe Buxbaum, directed the first prospective study on the effects of Shank3 deficiency on a subtype of autism called 22q13 Deletion Syndrome, also known as Phelan-McDermid Syndrome.

SFARI Gene

Source: 
SFARI
Date Published: 
February 21, 2013
Abstract: 

SFARI Gene is an integrated resource for the autism research community. It is a publicly available, curated, web-based, searchable database for autism research. This resource is built on information extracted from the studies on molecular genetics and biology of Autism Spectrum Disorders (ASD). The genetic information includes data from linkage and association studies, cytogenetic abnormalities, and specific mutations associated with ASD.

SFARI Reviews Mouse Models Used in Autism Genetics Research

Source: 
Simons Foundation Autism Research Initiative
Date Published: 
September 25, 2012
Abstract: 

New genetic variants that increase susceptibility to autism are emerging at a rapid pace from scans for copy number variants (CNVs) — deletions or duplications of DNA segments — and next-generation sequencing. Given the profusion of data, it seems timely to assess the availability and usefulness of mouse models in which to study these genetic risk factors.

Progress in Identifying the Genetic Roots of Autism

Source: 
Wall Street Journal
Date Published: 
September 25, 2012
Abstract: 

Genetic tests are beginning to shed light on the causes of some autism spectrum disorders.

Scientists Track Adult Regression in Autism-Related Syndrome

Source: 
Simons Foundation Autism Research Initiative
Date Published: 
July 26, 2012
Abstract: 

Scientists track adult regression in Phelan-McDermid Syndrome, which is one of the autism-related syndromes with an identified genetic basis.

Protein Interactome Reveals Converging Molecular Pathways

Source: 
Science Translational Medicine
Date Published: 
June 8, 2011
Year Published: 
2011

A recent study sheds light on how a variety of different mutations in genes that seemingly have little in common can each result in the symptoms of autism. To answer this question, researchers developed a molecular map of protein networks or "interactome" to identify how proteins associated with ASD interact with hundreds of other proteins. Researchers used genes known to be associated with syndromic autism as a starting point for building the interactome. Syndromic autism occurs as part of a broader genetic disorder such as fragile X, Angelman syndrome, and Rett syndrome -- understanding protein interactions with syndromic autism may give insight into idiopathic autism, or autism with no known cause. Using 26 genes associated with syndromic autism, researchers hypothesized that the seemingly dissimilar genes might interact with shared partners in common molecular pathways, leading to the symptoms of autism. Indeed, researchers identified a complex network of 539 proteins that interacted with the autism-related proteins, successfully demonstrating that all of the proteins linked to autism are connected by interactions with common partners. The interactome confirmed previously suspected gene relationships and several new pairings, such as the connection between SHANK3 and TSC1, which share 21 common protein partners. Researchers then performed a microarray analysis on 288 individuals with idiopathic autism in a search for genes within the interactome. They identified three novel copy number variations -- chromosomal deletions and duplications -- on genes found in the network, demonstrating that the interactome may help to identify new genes related to ASD and understand complicated genetic variation.

--IACC 2011 Summary of Advances in ASD Research