Autism Gene Alters Synapse Development

Variants in a gene, DIXDC1, have been found to impair the development of neural connectivity. The variants, which appear to contribute to autism spectrum disorders (ASDs), code for proteins that are equipped with what amounts to an on/off switch. Ordinarily, the DIXDC1 protein can be switched “on” via phosphorylation. Variant forms of the DIXDC1 protein, however, tend to stay “off.”

The consequences of being stuck on “off” can be dire, as demonstrated in a recent study by scientists based at McMaster University. These scientists, led by Karun Singh, Ph.D., report that ASD variants in DIXDC1 dysregulate dendrite and spine development, preventing changes in neuronal morphology and thereby impeding the maturation of synaptic connections.

Details of the scientists’ work appeared November 8 in the journal Cell Reports, in an article entitled, “DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants.” The article describes how the scientists used a knockout mouse model to determine that DIXDC1 is a regulator of excitatory neuron dendrite development and synapse function in the cortex.

“We discovered that MARK1, previously linked to ASDs, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner,” wrote the article’s authors. “Finally, rare missense variants in DIXDC1 were identified in ASD patient cohorts via genetic sequencing. Interestingly, the variants inhibit DIXDC1 isoform 1 phosphorylation, causing impairment to dendrite and spine growth.”

These findings could provide new insights into ASD that will guide identification of new medications for people with ASD. This is critical because ASD affects one in 68 individuals, and there are no medications that target the core symptoms of this complex disorder.

“Because we pinpointed why DIXDC1 is turned off in some forms of autism, [we now have] the opportunity to begin the searching for drugs that will turn DIXDC1 back on and correct synaptic connections,” said Dr. Singh. “This is exciting because such a drug would have the potential to be a new treatment for autism.”

While this discovery holds promise, mutations in DIXDC1 account for only a small number of individuals with autism and related psychiatric conditions, noted Dr. Singh.

“However, there is strong evidence that many other autism genes disrupt the development of synapses similar to DIXDC1,” she continued. “Therefore, the key to a new treatment for autism will be to find safe medications that restore brain cell synapse growth and activity.”