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 Could this protein protect people against coronary artery disease?
17.11.2017 | University of North Carolina Health Care

nachricht Microbial resident enables beetles to feed on a leafy diet
17.11.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

NASA detects solar flare pulses at Sun and Earth

17.11.2017 | Physics and Astronomy

NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures

17.11.2017 | Health and Medicine

The importance of biodiversity in forests could increase due to climate change

17.11.2017 | Studies and Analyses

VideoLinks
B2B-VideoLinks
More VideoLinks >>>