New autism genetic pathway discovered.

autism network1A new study has been released which specifies just how little researchers know of autism and other neurological diseases. The research published in the Journal of Nature Communications has uncovered gene networks that directly impact on autism. One of the autism related gene pathways also affects attention-deficit hyperactivity disorder (ADHD) and schizophrenia. Autism spectrum disorders (ASDs), consists of a diverse group of heritable childhood neuropsychiatric conditions characterized by impaired social interaction and communication, as well as by restricted behaviors. The study authors note specify that some recent investigations suggest that up to 400 distinct ASDs exist.

“Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically,” said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP). “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.”

The research consisted of a genome-wide association study which analyzed 6,700 patients with ASD to over 12,500 control subjects. This study is one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are defined as deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.

In autistic genes the research team found three groups of disrupted genes which act on biological pathways. Researchers paid special attention to the metabotropic glutamate receptor (mGluR) signaling pathway, defined by the GRM family of genes that affects the neurotransmitter glutamate, a major chemical messenger in the brain regulating functions such as memory, learning, cognition, attention and behavior.

The three gene families found in the current study have distinct functional roles. The CALM1 network defined by the calmodulin family of proteins, which regulate cell signaling and neurotransmitter function. The MXD-MYC-MAX gene network is involved in cancer development, and may underlie links reported between autism and specific types of cancer. Members of the GRM gene family affect nerve transmission, neuron formation, and interconnections in the brain—processes highly relevant to ASDs.

The functional activities identified are similar to a recent multicenter study in which Hakonarson participated, published May 1 in the American Journal of Human Genetics. That study determined that were hundreds of rare ASD-related gene variants converging on gene networks involved in neuronal signaling, synapse function and chromatin regulation (a biological process affecting gene expression).

“Even though our own study was large, it captures only about 20 percent of genes causing ASDs,” said Hakonarson, who added that still larger studies are needed to further unravel the genetic landscape of autism. “However, strong animal data support an important role for the glutamate receptor pathway in socially impaired behaviors modeling 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.”


Hakon Hakonarson, M.D., Ph.D. 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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