For years, autism has been noted in individuals with tuberous sclerosis, leading researchers to speculate that the two disorders may develop after troubles in the same biological pathway. Vijaya Ramesh and her colleagues at Massachusetts General Hospital are pursuing this lead by investigating whether genes linked to tuberous sclerosis are also associated with autism spectrum disorders.

The TOR pathway, which is named after a key protein that receives information on the cell surface, controls the growth of many cells and regulates the connections neurons make with each other. Mutations that remove regulators of the TOR pathway are associated with tuberous sclerosis. Ramesh hypothesizes that disruptions in this pathway may also cause the neuronal abnormalities that lead to autism.

Ramesh and her colleagues are examining the genes of several components of the TOR pathway, looking for rare variations that are associated with autism. By narrowing their focus, the researchers will be able to analyze more samples drawn from the Simons Simplex Collection, with a greater attention to detail in the candidate genes. Once one mutation is linked to autism, the researchers can try to find the mutation among more people with autism to make the correlation stronger. The team will also perform assays in cultured neurons to see how the mutations affect TOR pathway activity.

The investigators have adopted a two-tier pooling strategy wherein 10 DNA pools each of 300 patients (30 samples per pool) and 600 control samples (60 samples per pool) have been assembled. After completing sequencing of the 300 patient samples and 600 controls, the researchers plan to identify rare variations that are specific to autism samples. In future studies, they aim to confirm the identified variants in additional samples and validate these variants in functional assays using cultured neurons. This work will potentially identify novel pathways and strategies for autism treatment.