Rare Variants Could Act as Risk Factors for Schizophrenia

People with schizophrenia may seem like they have lost touch with reality. Although schizophrenia is not as common as other mental disorders, the symptoms can be very disabling. Schizophrenia is a complicated disease that often appears in early adulthood. Although scientists have not traced the genetic causes, more than 80% of schizophrenia cases are considered to have a hereditary cause. In a new report published in Translational Psychiatry, Japanese researchers report that a rare genetic variant, RTN4R, may have a fundamental role in the disease.

"Schizophrenia is a disease caused by disturbances in neural circuits. Myelin-related genes are associated with the disease," explains Osaka University Professor Toshihide Yamashita, one of the authors of the studies. Myelin acts as a conductor of signals for the neural circuits. Yamashita hypothesized that myelin-related genes could contribute to the pathology of schizophrenia.

RTN4R is a subunit of RTN4, which regulates crucial functions for neural circuits, namely, axon regeneration and structural plasticity.

Moreover, "RTN4 is a promising candidate gene for schizophrenia because it is located at chromosome 22q11.2, a hotspot for schizophrenia," he said.

Rare variants describe mutations that have low frequency but a large effect. Yamashita and his colleagues searched for rare variants of RTN4. Screening the DNA of 370 schizophrenia patients, he found a single missense mutation, R292H, that changed the amino acid of this protein from arginine to histidine in two patients.

R292H is located in the domain of RTN4R that binds to ligands, so a change in even a single amino acid could have profound effects on RTN4 function (Figure 1). To test this possibility, the scientists expressed the mutation in chick retinal cells, which only weakly express the gene, finding a significant change in myelin-dependent axonal behavior (Figure 2). Computer simulations showed that the mutation reduced the interaction between RTN4 and its partner protein, LINGO1, by increasing the distance between the two.

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Yamashita is convinced that rare variants could act as risk factors for schizophrenia.

"There is growing evidence that rare variants contribute to neurodevelopment diseases. The R292H mutation was not found in any existing databases. Our findings strengthen the evidence that rare variants could contribute to schizophrenia," he said.

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Source-Eurekalert