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Autism spectrum disorders: potential gene network targets
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Analysis of copy number variations, which are deletions or insertions in DNA, has revealed that several defective gene family interaction networks (GFINs) are potentially involved in autism spectrum disorders. The genome-wide association study’s results were published on 6th June in the journal Nature Communications. The study was led by researchers in the Center for Applied Genomics at The Children's Hospital of Philadelphia and has implications for development of new drugs for autism-spectrum disorders or re-purposing of existing drugs that target these networks.

Autism-spectrum disorders, of which autism is the best known, are heritable, childhood, neurological conditions that feature impairment in social interaction and communication as well as restricted behaviours. In the current study, the research team compared copy number variants from the DNA of over 6700 autism-spectrum disorder patients to that of over 12,500 healthy control subjects. The results indicated defects in several gene family interaction networks, including three in which the gene variant affects gene-protein interactions.

Of particular interest was the metabotropic glutamate receptor (mGluR), a member of the GRM family which helps mediate signalling by the neurotransmitter glutamate. This neurotransmitter is involved in memory, learning, cognition, attention and behaviour. The research team had previously shown that CNVs in GRM genes are prevalent in attention deficit disorder patients while others had shown GRM defects in schizophrenia. Thus despite the heterogeneous nature of these neurological disorders, all of them may be amenable to drugs targeting the GRM family. Senior author Dr Hakon Hakonarson explains: "Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically…However, the common biological patterns we are finding across disease categories strongly imply that focusing on underlying molecular defects may bring us closer to devising therapies."

Defects were also observed in other important gene families. These included the CALM1 network which includes calmodulin proteins, responsible for cell signalling regulation and neurotransmitter function. They also included the MXD-MYC-MAX gene network which is linked to cancer and may contribute to the observed association between some cancer types and autism.

The GRM findings from this and the group’s previous study has prompted Dr Hakonarson to begin a clinical trial in selected ADHD patients of a GRM pathway-activating drug. Dr Hakonarson says: "If drugs affecting this pathway prove successful in this subset of patients with ADHD, we may then test these drugs in autism patients with similar gene variants." In autism-spectrum disorders and other neurological conditions, the genetic picture is complex, with common gene variants often exerting only small individual effects while rare variants exert stronger influence, which may offer targets for new or re-purposed drugs. Dr Hakonarson cautions that even larger studies are needed to continue to unravel the genetics behind these condtions. He concludes: "Even though our own study was large, it captures only about 20 percent of genes causing…However, strong animal data support an important role for the glutamate receptor pathway in socially impaired behaviours modelling ASDs. Because the GRM pathway seems to be a major driver in three diseases-- autism, ADHD and schizophrenia--there is a compelling rationale for investigating treatment strategies focused on this pathway."

Sources:

Press release: Children's Hospital of Philadelphia; available from: http://www.eurekalert.org/pub_releases/2...060414.php [Accessed 6 June 2014]

Hakonarson, H. et al. The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism. Nature Communications, June 2014 DOI: 10.1038/ncomms5074
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Autism spectrum disorders: potential gene network targets00