Many single-gene disorders linked to autism affect proteins that modulate the translation of messenger RNA into proteins that function at synapses, the junctions between neurons. A few examples are FMRP in fragile X syndrome, TSC1 and TSC2 in tuberous sclerosis complex and PTEN in Cowden syndrome. This led Mark Bear at the Massachusetts Institute of Technology and Raymond Kelleher at Massachusetts General Hospital to propose that ‘troubled translation’ is a core pathophysiological mechanism underlying autism spectrum disorders.

This hypothesis is supported by studies of mice lacking FMRP (modeling fragile X syndrome) or mice in which one copy of TSC2 is deleted (modeling tuberous sclerosis complex). The basal rate of protein synthesis is altered in both of these model mice. However, the defect can be rectified through genetic or pharmacological treatment, which ameliorates synaptic function and corrects behavioral abnormalities.

A microdeletion at human chromosome 16p11.2 is one of the most common copy number variations in autism spectrum disorders. A mouse model of this microdeletion (the chr7qF3-deficient mouse) shows behavioral phenotypes similar to some behavioral abnormalities and comorbidities associated with autism. However, the pathophysiological and biochemical mechanisms underlying these behavioral phenotypes remain unexplored.  Bear and his research team aim to test whether the 16p11.2 model mice share some pathophysiology with mice lacking FMRP. If their hypothesis is correct, treatment strategies being developed for fragile X syndrome could be adopted for treating autism.