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Researchers Find Rare Mutations in SHANK3 Gene Are Associated with Autism

Results Help Focus on Synaptic Functioning as a Critical Pathway in the Biology of Autism
September 13, 2007

An international team of researchers headed by Thomas Bourgeron, Ph.D., has identified a set of mutations in a gene called SHANK3. Dr. Bourgeron's research team associated the SHANK3 mutations with Autism Spectrum Disorders in a recent study funded by Cure Autism Now and published in the

January issue of the journal Nature Genetics. Although the identified mutations were found in only a few of the families studied, their results are revealing because they help to construct a biological pathway that may underlie the deficits of autism. Ultimately, it is the identification of the disrupted biological processes that will provide the basis for a targeted treatment design.

The SHANK3 gene codes for a protein that is involved in the formation and maintenance of synapses. Synapses are the points of communication between neurons and are critical for the proper functioning of the nervous system. Depending on its location and function, a single neuron can synapse with (and therefore communicate with) 100's or even 1000's other neurons. The network of synapses between neurons in the brain allows for the collective of electrical signaling required for complex functions, such as cognition and language.

Genes that control the function and architecture of synapses were previously targeted by Dr. Bourgeron as possible candidates for mutation in autism. In 2004, Dr. Bourgeron and colleagues discovered that rare mutations in a family of genes known as the Neuroligins were associated with autism spectrum disorders. The Neuroligin genes are responsible for making proteins called neuroligins. Like the SHANK3 protein, the neuroligins are involved in building and maintaining synapses and are therefore important for the overall communication processes between neurons in the brain.

Because the Neurologin and SHANK3 proteins physically interact with each other at synapses in the brain, Dr. Bourgeron's team hypothesized that mutations in either of these genes could impair the synaptic architecture required for the development of complex functions such as social communication and language. These new findings now provide additional evidence that a key pathway involved in generating autism is likely to be found in the intricate network of synaptic proteins that orchestrate nerve cell communication.

In their newest study, the researchers were guided by the fact that a particular area of the human genome, a region known as chromosome 22q13.3, has been shown to harbor abnormal deletions in individuals with cognitive deficits. The "22q13.3 microdeletion syndrome" is characterized by global developmental delay, normal or accelerated growth, delayed or absent speech, and other autistic behaviors. Although there are several genes in the 22q13.3 region of the genome, recently the cause of the 22q13.3 microdeletion syndrome has been pinpointed to mutations in the gene SHANK3. Given the overlap of 22q13.3 microdeletion syndrome with autistic behaviors, and the functional interaction between the SHANK3 and neuroligin proteins, Dr. Bourgeron and his team now sought to examine the SHANK3 gene for a direct role in cases of autism.

Dr. Bourgeron and his colleagues used very detailed methods to screen over three hundred individuals with autism spectrum disorders in order to detect any type of small scale chromosomal abnormality or DNA sequence change. Three families with important changes were identified. In two of these families, one copy of the gene was damaged, leading to formation of a disrupted SHANK3 protein in the affected individuals. All of the children carrying these mutations had been diagnosed with autism and had severely disrupted language. In the remaining family, one child with autism and language delay was found to be missing a copy of the gene, while their sibling with Asperger's and precocious language development, was actually found to have an extra copy of the gene. These results clearly reveal that changes in the SHANK3 gene can be associated with autism spectrum disorders. Additionally, it suggests that the synaptic pathway in which SHANK3 operates is very sensitive to the number of copies ("dosage") of the gene, and that language and cognitive defects can result if the pathway is disturbed in any way.

SHANK3 protein is known to be a key structural component of the machinery required for nerve cells to build synapses. Therefore, the researchers carefully tested one of the mutated SHANK3 proteins for its ability to form proper synapses. While they confirmed that the normal SHANK3 protein was readily able to form the synaptic structures necessary to make nerve cell connections, the altered (mutated) SHANK3 protein that came from one of the families was unable to form these structures. These results support the idea that the SHANK3 gene mutations could have had functional consequences upon the development of brain circuitry in those individuals that carry these mutations.

Although mutations in SHANK3 were found in only about 1% of the individuals examined, the results likely have wider consequence. An additional seven families with autism had variations in the gene, which may or may not be significant to the function of the protein, but which the authors speculate may represent risk factors for autism in conjunction with additional susceptibility factors. More importantly, although the total number of families affected by either SHANK3 or Neuroligin mutations may each be very small, because they both have similar functions, the results suggest that interfering with synaptic structures -- whether it be through defects in SHANK3, neuroligin, or any of the other proteins that act in the same complex – may result in the development of autism.

The causes of autism are likely to be multifactorial, involving both genetic and non-genetic triggers. Once the causal biological pathways are discovered, researchers can start designing treatments that directly target the disturbed pathways and compensate for them. When reached for comment, Dr. Bourgeron summarized his newest findings by explaining that “these mutations are not so important because of the number of people that have them, but because of what they reveal about the biology of autism. The presence of mutations in both SHANK3 and Neuroligin is telling us that the synaptic pathway is one on which we need to be concentrating.”

For further reading on this subject:

Durand CM et al. (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet, 39(1):25-7.

Persico AM and Bourgeron T. (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci, 7:349-58.

Jamain, S et al. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet, 34(1):27-9.

Zoghbi, HY. (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science,302(5646):826-30.