Researchers have long identified that autism spectrum disorders are correlated to a group of genes. Now for the first time researchers have identified the specific function of one gene linked to Autism.
Scientists at the John Hopkins University School of Medicine and Tel Aviv University have identified a mutation in the NEH9 gene, 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.”
The NHE9 gene is 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 research team wondered how this function might be related to neurological conditions.
To evaluate the gene function, Scientists constructed a computer model of the NEH9 protein based on prior research of a distant bacterial relative. They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein’s shape and function.
The second step in the gene functionality testing involved 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.
The team selected the mutations that had a detectable effect on the yeast, and moved onto brain cells in mice brains. They specifically examined 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 modified 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. As 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.
Kalyan C. Kondapalli, Anniesha Hack, Maya Schushan, Meytal Landau, Nir Ben-Tal, Rajini Rao. Functional evaluation of autism-associated mutations in NHE9. Nature Communications, 2013; 4 DOI: 10.1038/ncomms3510