Genetic clues could aid precision care for psychiatric disorders microbiologystudy

For patients with disorders such as autism and schizophrenia, mutations in the same gene could require different treatments, according to new research from Yale School of Medicine (YSM).

Many psychiatric and neurodevelopmental disorders are highly influenced by genetics. As much as 80% of the risk of developing schizophrenia and autism can be attributed to genetics, although many of the responsible genes have not yet been identified. Even among known genes associated with these conditions, the mechanism by which mutations in the same gene can result in vastly different outcomes—thus requiring vastly different treatments—remains unclear.

By studying mutations in a gene called neurexin-1, which is highly associated with both schizophrenia and autism, researchers from Yale and the Icahn School of Medicine at Mount Sinai discovered that different types of mutations in the gene required different treatments. Their study, published in Nature on April 9, holds important implications for precision medicine.

“If you’re talking about precision medicine, you’re targeting shared gene mutations between patients, rather than starting with a symptom-first approach,” says Kristen Brennand, Ph.D., Elizabeth Mears and House Jameson Professor of Psychiatry at YSM and co-principal investigator of the study.

“What we’re doing is diving even further and saying it’s not just enough to target the gene mutation. You also have to target it with the right mechanism depending on the gene mutation.”

Gang Fang, Ph.D., professor of genetics, and Paul Slesinger, Ph.D., Lillian and Henry M. Stratton Professor of Neuroscience, both of Icahn School of Medicine at Mount Sinai, served as co-principal investigators of the study with Brennand.

Different mutations affect excitatory and inhibitory neurons

While rare, mutations that remove or delete sections of DNA in neurexin-1, called deletion mutations, are highly associated with schizophrenia and autism. But these mutations are not straightforward. Almost all affected patients have deletions in different parts of the gene, and because neurexin-1 can code for hundreds of different proteins, deletions in different regions of the gene will affect different proteins.

“This idea of stratifying not just based on symptoms but on genetics and the type of mutations is really the big take home for informing future precision medicine,” Brennand says.

In a previous study, Brennand and her team identified that some neurexin-1 deletion mutations in neurons can cause a loss of function: Patients with the mutations were missing about half of the proteins that should have come from neurexin-1. But they also found that a different deletion mutation in neurexin-1 could actually cause a gain of function, resulting in new proteins that would never be seen in healthy neurons.

The researchers examined these findings further in the new study, using skin cells from four patients with psychosis who all had neurexin-1 mutations: two patients with the same loss of function mutation, and two patients with the same gain of function mutation. They reverted these skin cells to stem cells and then turned stem cells from each patient into either glutamatergic neurons, which are responsible for excitatory signaling in the brain, or GABAergic neurons, which are responsible for inhibitory signaling, to see how the different mutations would affect both types of neurons.

Experiments led by Michael Fernando, Ph.D., first author of the study and recent graduate of the Icahn School of Medicine at Mount Sinai, revealed that both the gain of function mutation and the loss of function mutation caused decreased activity in glutamatergic neurons, but increased activity in GABAergic neurons.

“The glutamatergic neurons are firing less, and the neurons that turn other neurons off—the GABAergic neurons—are firing more, which would in turn make the glutamatergic neurons fire even less in the brain,” Brennand says. “It’s a double hit.”

While the research used neurons derived from stem cells, which are not fully representative of the developed human brain, the findings still demonstrate how different mutations affect brain cell function.

Rescuing mutations informs precision medicine for both autism and schizophrenia

While the two different mutations caused the same outcomes in both neuron types—decreased activity in glutamatergic and increased activity in GABAergic—they did so through different mechanisms. Therefore, counteracting these effects required different approaches for each mutation.

For loss of function mutations, the researchers were able to rescue effects using estradiol, which binds to estrogen receptors to promote increased neurexin-1 expression. But for the gain of function mutations, they used pieces of DNA that can intervene and halt the protein creation process.

“The idea is that if you have precision medicine, it’s not enough just to rescue the loss of function, we also have to rescue the gain of function when it happens,” Brennand says. “We’ve shown that you could independently rescue both loss of function and gain of function mechanisms in neurexin-1.”

Brennand believes that this work could extend far beyond neurexin-1, creating new considerations for precision medicine approaches to treat other genetic mutations associated with autism and schizophrenia, and potentially other brain-related conditions, such as epilepsy, Timothy Syndrome, and frontotemporal dementia.

“There are at least a dozen or more other genes where some patients have loss of function and others have gain of function, so it is informing us as we move toward precision medicine,” Brennand says. “Thinking about stratifying patients on their exact genetics is probably what has to happen moving forward.”