Japanese scientists have identified a rare gene variant that plays a fundamental role in increasing the risk of schizophrenia - a chronic and severe mental disorder which affects how a person thinks, feels and behaves.
Schizophrenia is a complicated disease that often appears in early adulthood. Although scientists have not traced the genetic causes, more than 80 per cent of schizophrenia cases are considered to have a hereditary cause.
"Schizophrenia is a disease caused by disturbances in neural circuits. Myelin-related genes are associated with the disease," said Toshihide Yamashita, a professor at the Osaka University in the Japan.
Myelin acts as a conductor of signals for the neural circuits. Yamashita hypothesised that myelin-related genes could contribute to the pathology of schizophrenia.
The rare genetic variant, RTN4R, is a subunit of RTN4, which regulates crucial functions for neural circuits, namely, axon regeneration and structural plasticity.
"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.
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 behaviour.
Computer simulations showed that the mutation reduced the interaction between RTN4 and its partner protein, LINGO1, by increasing the distance between the two.
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.
The research was published in the journal Translational Psychiatry.