Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Three gene networks discovered in autism, may present treatment targets

06.06.2014

CHOP research points to brain's glutamate signaling in autism, ADHD, schizophrenia

A large new analysis of DNA from thousands of patients has uncovered several underlying gene networks with potentially important roles in autism. These networks may offer attractive targets for developing new autism drugs or repurposing existing drugs that act on components of the networks.

Furthermore, one of the autism-related gene pathways also affects some patients with attention-deficit hyperactivity disorder (ADHD) and schizophrenia—raising the possibility that a class of drugs may treat particular subsets of all three neurological disorders.

"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."

... more about:
»ADHD »ASDs »Autism »CNVs »defects »drugs »genes »glutamate »networks »pathway »variants

The study by Hakonarson and colleagues, appearing online today in Nature Communications, draws on gene data from CHOP's genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks.

Autism spectrum disorders (ASDs), of which autism is the best known, are a large group of heritable childhood neuropsychiatric conditions characterized by impaired social interaction and communication, as well as by restricted behaviors. The authors note that recent investigations suggest that up to 400 distinct ASDs exist.

The current research is a genome-wide association study comparing more than 6,700 patients with ASDs to over 12,500 control subjects. It was one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.

The study team focused on CNVs within defective gene family interaction networks (GFINs)—groups of disrupted genes acting on biological pathways. In patients with autism, the team found three GFINs in which gene variants perturb how genes interact with proteins. Of special interest to the study group was 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.

Hakonarson's team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the glutamate receptor metabotropic (GRM) pathway, while other teams have implicated GRM gene defects in schizophrenia.

Based on these findings, Hakonarson is planning a clinical trial in selected ADHD patients of a drug that activates the GRM pathway. "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," he said.

In ASDs and other complex neurodevelopmental disorders, common gene variants often have very small individual effects, while very rare gene variants exert stronger effects. Many of these genes with very rare defects belong to gene families that may offer druggable targets.

The three gene families found in the current study have notable functional roles. The CALM1 network includes 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. Finally, 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 in the current study are consistent with a recent multicenter study in which Hakonarson participated, published May 1 in the American Journal of Human Genetics. That study, led by scientists from Paris and Toronto, and using Autism Genome Project data, found 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). Many of the genes in these networks have been implicated in other developmental disorders besides autism.

"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."

###

The AGRE Consortium, a program of Autism Speaks, provided resources and data for this study. AGRE is supported in part by the National Institutes of Health (including grant MH081810).

"The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism," Nature Communications, published online June 6, 2014. http://doi.org/10.1038/ncomms5074

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program receives the highest amount of National Institutes of Health funding among all U.S. children's hospitals. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

John Ascenzi | Eurek Alert!

Further reports about: ADHD ASDs Autism CNVs defects drugs genes glutamate networks pathway variants

More articles from Life Sciences:

nachricht Severity of enzyme deficiency central to favism
26.07.2016 | Universität Zürich

nachricht From vision to hand action
26.07.2016 | Deutsches Primatenzentrum GmbH - Leibniz-Institut für Primatenforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Self-assembling nano inks form conductive and transparent grids during imprint

Transparent electronics devices are present in today’s thin film displays, solar cells, and touchscreens. The future will bring flexible versions of such devices. Their production requires printable materials that are transparent and remain highly conductive even when deformed. Researchers at INM – Leibniz Institute for New Materials have combined a new self-assembling nano ink with an imprint process to create flexible conductive grids with a resolution below one micrometer.

To print the grids, an ink of gold nanowires is applied to a substrate. A structured stamp is pressed on the substrate and forces the ink into a pattern. “The...

Im Focus: The Glowing Brain

A new Fraunhofer MEVIS method conveys medical interrelationships quickly and intuitively with innovative visualization technology

On the monitor, a brain spins slowly and can be examined from every angle. Suddenly, some sections start glowing, first on the side and then the entire back of...

Im Focus: Newly discovered material property may lead to high temp superconductivity

Researchers at the U.S. Department of Energy's (DOE) Ames Laboratory have discovered an unusual property of purple bronze that may point to new ways to achieve high temperature superconductivity.

While studying purple bronze, a molybdenum oxide, researchers discovered an unconventional charge density wave on its surface.

Im Focus: Mapping electromagnetic waveforms

Munich Physicists have developed a novel electron microscope that can visualize electromagnetic fields oscillating at frequencies of billions of cycles per second.

Temporally varying electromagnetic fields are the driving force behind the whole of electronics. Their polarities can change at mind-bogglingly fast rates, and...

Im Focus: Continental tug-of-war - until the rope snaps

Breakup of continents with two speed: Continents initially stretch very slowly along the future splitting zone, but then move apart very quickly before the onset of rupture. The final speed can be up to 20 times faster than in the first, slow extension phase.phases

Present-day continents were shaped hundreds of millions of years ago as the supercontinent Pangaea broke apart. Derived from Pangaea’s main fragments Gondwana...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

GROWING IN CITIES - Interdisciplinary Perspectives on Urban Gardening

15.07.2016 | Event News

SIGGRAPH2016 Computer Graphics Interactive Techniques, 24-28 July, Anaheim, California

15.07.2016 | Event News

Partner countries of FAIR accelerator meet in Darmstadt and approve developments

11.07.2016 | Event News

 
Latest News

New movie screen allows for glasses-free 3-D

26.07.2016 | Information Technology

Scientists develop painless and inexpensive microneedle system to monitor drugs

26.07.2016 | Health and Medicine

Astronomers discover dizzying spin of the Milky Way galaxy's 'halo'

26.07.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>