Gene Mutation Increases Risk of Neurodevelopmental Disorders

Researchers have found that a rare variant of the G protein-coupled receptor CX3CR1, due to only a single amino acid substitution, may become useful in predicting increased risk for developing schizophrenia and autism.

Huntington's disease, cystic fibrosis, and muscular dystrophy are diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy: you have the mutation? Then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. The new study, led by researchers at Nagoya University (Nagoya, Japan) and Osaka University (Osaka, Japan), have found a rare mutation that could act as a predictor for schizophrenia and autism.


"Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism," said paper co-author Toshihide Yamashita, professor at Osaka University, "Microglia contribute to the structure and function of synapse connectivities." Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. They have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders.

Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7000 schizophrenia and autism patients and healthy subjects, finding that one mutant candidate, a single amino acid switch from alanine to threonine, is a rare variant and a candidate marker for prediction. “Rare variants alter gene function but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause,” said Prof. Yamashita.

The structure of CX3CR1 includes a Helix-8 domain that is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling. "The variant changes the region from hydrophobic to hydrophilic and destabilizes Helix 8. We overexpressed the mutation in cells and found Akt signaling was disrupted," explained Prof. Yamashita, adding that the findings are the first to connect a genetic variation in microglia with neurodevelopment disorders.

He hopes the discovery could become a basis for predictive diagnostics: "There is no reliable way to diagnose schizophrenia or autism in asymptomatic patients. Deeper understanding of the genetic risk factors will help us develop preventative measures," said Prof. Yamashita.

The study, by Ishizuka K et al, was published August 1, 2017, in the journal Translational Psychiatry.

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Nagoya University
Osaka University