A rare genetic finding shows that GRIN2A mutations can directly trigger psychiatric illness. Early treatment insights point to new paths for intervention.
For many years, scientists believed that conditions such as schizophrenia, anxiety disorders, or depression developed through a combination of numerous influences, including heredity. A new international study led by the Institute of Human Genetics at the University of Leipzig Medical Center now shows for the first time that a change in a single gene can directly cause a mental disorder. The findings were recently published in the journal Molecular Psychiatry.
The World Health Organization (WHO) reports that in 2021, nearly one in seven people worldwide was living with some form of mental illness, with anxiety disorders and depression appearing most often. These disorders usually stem from a complex mix of causes in which genetics play a major role.
Having a close relative with a mental illness is considered one of the strongest known risk factors. Earlier research generally proposed that mental disorders develop only when many genetic factors interact.
GRIN2A identified as a single-gene driver
“Our current findings indicate that GRIN2A is the first known gene that, on its own, can cause a mental illness. This distinguishes it from the polygenic causes of such disorders that have been assumed to date,” says Professor Johannes Lemke, lead author of the study and Director of the Institute of Human Genetics at the University of Leipzig Medical Center.
The research team examined data from 121 individuals who carried a change in the GRIN2A gene. “We were able to show that certain variants of this gene are associated not only with schizophrenia but also with other mental illnesses. What is striking is that, in the context of a GRIN2A alteration, these disorders already appear in childhood or adolescence – in contrast to the more typical manifestation in adulthood,” Professor Lemke explains. The researchers also noted that some individuals showed only psychiatric symptoms, even though GRIN2A changes are usually linked to epilepsy or intellectual disability.
Mechanistic insights and therapeutic potential
The GRIN2A gene plays a central role in regulating the electrical excitability of nerve cells. In the present study, certain variants led to reduced activity of the NMDA receptor, a key molecule in signal transmission in the brain. Together with Dr Steffen Syrbe, Professor at the Heidelberg Medical Faculty and pediatric neurologist at Heidelberg University Hospital, the clinicians showed that this aspect could also be therapeutically relevant: in an initial treatment series, patients showed marked improvements in their psychiatric symptoms following therapy with L-serine – a dietary supplement that activates the NMDA receptor.
Professors Johannes Lemke and Steffen Syrbe have been working together for almost 15 years, in both research and clinical practice, on disorders of the glutamate receptor in the brain in children with neurological diseases. During this time, Professor Lemke has established an international registry that comprises the world’s largest cohort of GRIN2A patients, which formed the basis for the current publication.
Reference: “GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy” by Johannes R. Lemke, Andrea Eoli, Ilona Krey, Bernt Popp, Vincent Strehlow, Dirk A. Wittekind, Anna-Leena Vuorinen, Hesham M. Aldhalaan, Sarah Baer, Anne de Saint Martin, Trine B. Hammer, Isabella Herman, Frauke Hornemann, Trine Ingebrigtsen, Damien Lederer, Gaetan Lesca, Dana Marafie, Mikael Mathot, Jill A. Rosenfeld, Rikke S. Møller, Helenius J. Schelhaas, Chelsey Stillman, Alessandro Orsini, Anup D. Patel, Juliette Piard, Pierangelo Veggiotti, Danique R. M. Vlaskamp, Sarah Weckhuysen, Stephen F. Traynelis, Tim A. Benke, Henrike O. Heyne and Steffen Syrbe, 14 October 2025, Molecular Psychiatry.
DOI: 10.1038/s41380-025-03279-4
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