Rare Gene Mutation May Explain Cause of Mental Disorders

A recent study has shown how a rare mutation in a suspect gene disrupts the turning on and off of dozens of other genes underlying neuron connections, which may help explain the root of major mental disorders. Findings from this study are reported in the journal Nature.

Hongjun Song, PhD, of Johns Hopkins University, in Baltimore, MD, and colleagues used a disease-in-a-dish technology called induced pluripotent stem cells (iPSCs). This involves initially reverting a patient's skin cells into stem cells. In this experiment, these reverted stem cells were coaxed to differentiate into neurons, which could be studied developing and interacting in a petri dish.

Song and colleagues studied iPSCs from four members of an American family affected by DISC1-linked schizophrenia and genetically related mental disorders. Researchers discovered that iPSC-induced neurons of a type linked to psychosis expressed 80% less of the protein made by the DISC1 gene in family members with the mutation vs. members without the mutation. The corrupted neurons showed a lack of communication with other neurons at synapses.

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The team was also able to produce the synapse deficits by genetically engineering the DISC1 mutation into normal iPSC neurons. The synapse deficits in DISC1 mutant iPSC neurons were corrected by genetically engineering a fully functional DISC1 gene into them. This demonstrated that the DISC1 mutation was the cause of the deficits.

In general, these findings suggest a common disease mechanism in major mental illnesses that combine genetic risk, abnormal neurodevelopment, and synapse dysfunction.

For more information visit NIH.gov.

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