Research Team first to Map Autism-Risk Genes by Function

Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to increased autism risk. Where do you start?

UCLA neuroscientists may have an answer. They are the first to map groups of autism-risk genes by function, and to identify where and when these genes normally play major roles in early brain development.

In addition, they discovered disturbances in neural circuits that define key pathways between parts of the cerebral cortex.

The research suggests that these early disruptions are created by mutations in genes during fetal brain development and are not a result of autism itself.

Published in the Nov. 21 edition of Cell, the findings will help scientists understand how genetic changes cause autism on a molecular level and prioritize targets for future studies.

"Identifying gene variants that boost risk is only the first step of unraveling a disease," explained lead author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behaviour.

"We need to figure out where genetic changes appear in the brain, at what stages during development and which biological processes they disrupt. Only then will we understand how mutations cause autism."

Using an online atlas called BrainSpan, the authors charted gene activity in the developing brain before birth.

In particular, they examined what happens during gene expression —when genes copy data from DNA to RNA in order to create proteins.

Geschwind and his colleagues found high activity in risk genes during two processes critical to early brain development.

"We found that gene variants are expressed in the developing brain when cells define their future identities and roles in neural circuits," first author Neelroop Parikshak, a graduate student researcher in Geschwind's lab.

"Therefore, changes in the genes influence the brain's wiring by altering the synapse and shaping how neurons transmit signals to each other."

The mutated genes also interfered with how the brain's layers and halves relate to one another, a phenomenon confirmed by previous imaging studies of the autistic brain.

"We discovered gene-related disruption of circuits that connect the autistic brain's layers and hemispheres to each other," explained Geschwind, who is director of the UCLA Neurogenetics Program and the Center for Autism Research and Treatment and co-director of the Center for Neurobehavioral Genetics at UCLA.

 "Our finding suggests that the mutated genes caused the miswiring; it's not a result of having the disease itself."

The UCLA team also demonstrated that while autism and intellectual disability share similar risk genes, the genes behave uniquely, showing for the first time how the two disorders differ.

"People often lump intellectual disability together with autism, because the disorders' risk genes overlap," said Parikshak.

"We showed that these genes have unique expression patterns in different brain regions at varying times during brain development.

"Genes linked to intellectual disability influence many biological processes in the body," he added. "But genes tied to autism tend to affect specific functions, such as the connections between brain regions that are essential to many human-specific behaviours, like speech and language."

The UCLA study will reap immediate benefits in the near future, when neuroscientists sequence the genomes of several thousand people for genetic mutations linked to autism and intellectual disability.

"We've made our analysis publically available to allow other researchers to expand upon our study and explore the data in detail," said Geschwind.

"We believe this will mark an important step forward in understanding the biology behind autism and other neurodevelopmental disorders."

Researchers ferret out function of autism gene

The structure of the protein NHE9 is one piece of the puzzle of what causes autism. 

Credit: Kalyan Kondapalli and Rajini Rao

Researchers say it's clear that some cases of autism are hereditary, but have struggled to draw direct links between the condition and particular genes.

Now a team at the Johns Hopkins University School of Medicine, Tel Aviv University and Technion-Israel Institute of Technology has devised a process for connecting a suspect gene to its function in autism.

In a report in the Sept. 25 issue of Nature Communications, the scientists say mutations in one such autism-linked gene, dubbed NHE9, which is involved in transporting substances in and out of structures within the cell, causes communication problems among brain cells that likely contribute to autism.

"Autism is considered one of the most inheritable neurological disorders, but it is also the most complex," says Rajini Rao, Ph.D., a professor of physiology in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.

"There are hundreds of candidate genes to sort through, and a single genetic variant may have different effects even within the same family. This makes it difficult to separate the chaff from the grain, to distinguish harmless variations from disease-causing mutations. We were able to use a new process to screen variants in one candidate gene that has been linked to autism, and figure out how they might contribute to the disorder."

An estimated one in 88 children in the United States is affected by autism spectrum disorders, a group of neurological development conditions marked by varying degrees of social, communication and behavioral problems.

Scientists for years have looked for the biological roots of the problem using tools such as genome-wide association studies and gene-linkage analysis, which crunch genetic and health data from thousands of people in an effort to pinpoint disease-causing genetic variants.

But while such techniques have turned up a number of gene mutations that may be linked to autism, none of them appear in more than 1 percent of people with the condition. With numbers that low, researchers need a way to screen variants in order to make a definitive link, Rao says.

For the new study, Rao and her collaborators focused on NHE9, which other researchers had flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders.

The gene was already known to be involved in transporting hydrogen, sodium and potassium ions in and out of cellular compartments called endosomes, and the team wondered how this function might be related to neurological conditions.

Rao's collaborators at Tel Aviv University and Technion-Israel Institute of Technology constructed a computer model of the NHE9 protein based on previous research on a distant relative in bacteria.

They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein's shape and function.

Some of them were predicted to cause dramatic changes, while other changes appeared to be more subtle.

Rao's team next tested how these variant forms of NHE9 would affect a relatively simple organism often used in genetic studies: yeast.

"Using yeast to screen the function of variants was a quick, easy and inexpensive way of figuring out which were worth further study, and which we could ignore because they didn't have any effect," Rao says.

To do that, the team engineered the yeast form of NHE9 to have the variants seen in autistic people.

For those mutations that did have a detectable effect on the yeast, the team moved on to a third and more challenging step, in mouse brains.

They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job of delivering a message across a synapse between two nerve cells.

Using lab-grown mouse astrocytes with variant forms of NHE9, the researchers found a change in the pH (acidity) inside cellular compartments called endosomes, which in turn altered the ability of cells to take up glutamate.

Because endosomes are the vehicles that deliver cargo essential for communication between brain cells, changing their pH alters traffic to and from the cell surface, which could affect learning and memory, Rao says.

"Elevated glutamate levels are known to trigger seizures, perhaps explaining why autistic patients with mutations in NHE9 and related genes also have seizures," she notes.

Rao and her team hope that pinpointing the importance of this trafficking mechanism in autism spectrum disorders may lead to the development of new drugs for autism that alter endosomal pH.

As the use of genomic data becomes increasingly commonplace in the future, the step-wise strategy devised by her team can be used to screen gene variants and identify at-risk patients, she says.

More information: www.nature.com/ncomms/2013/130925/ncomms3510/full/ncomms3510.html

Virtual Reality Improves Hand Function: Playing Games for Real Recovery

Remotely monitored in-home virtual reality videogames improved hand function and forearm bone health in teens with hemiplegic cerebral palsy, helping them perform activities of daily living such as eating, dressing, cooking, and other tasks for which two hands are needed.

"While these initial encouraging results were in teens with limited hand and arm function due to perinatal brain injury, we suspect using these games could similarly benefit individuals with other illness that affect movement, e.g. multiple sclerosis, stroke, arthritis and even those with orthopedic injuries affecting the arm or hand," said Meredith R. Golomb, M.D, M.Sc., Indiana University School of Medicine associate professor of neurology.

A pediatric neurologist at Riley Hospital for Children, she is the first author of a pilot study which reported on the rehabilitative benefits of these custom videogames.

The researchers also reported that improved hand function appears to be reflected in brain activity changes as seen on functional magnetic resonance imaging (fMRI) scans.

The three study participants were asked to exercise the affected hand about 30 minutes a day, five days a week using a specially fitted sensor glove linked to a remotely monitored videogame console installed in their home.

Games, such as one making images appear ("sliders") were custom developed, calibrated to the individual teen's hand functionality, included a screen avatar of the hand, and focused on improvement of whole hand function.

"Popular off-the-shelf games are targeted to people with normal hand and arm function and coordination. These games don't work for or benefit those with moderate-severe hemiplegic cerebral palsy and many other disorders that affect movement. They just aren't made to be used by or improve hands that can't pinch or grasp" said Dr. Golomb.

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