Functional analysis of EPHB2 mutations in autism

Abnormal brain wiring during early development may be a causal factor in autism spectrum disorders. Brain wiring requires the guidance of neuronal fibers (axons) to the appropriate brain regions, as well as the establishment of functional synapses — key points of communication between neurons.

Matthew State and Abha Gupta at Yale University have identified several rare, highly disruptive mutations in people with autism. They used samples from the Simons Simplex Collection, a collection of biospecimens and genetic data from 2,700 families in which one child has an autism spectrum disorder. One of the disrupted genes, EPHB2, is a strong candidate gene for autism risk. EPHB2 encodes a protein called EPHB receptor, which is a member of a family of cell-surface proteins that regulate brain development processes, including axon guidance, formation and remodeling of chemical synapses, and changes in synapse strength induced by experience.

In parallel studies, Christopher Cowan at McLean Hospital and Harvard Medical School is investigating the role of EPHB receptor genes in early brain development in mice. The Cowan lab has identified an essential role for EPHB receptors in axon guidance during early development of the cortex and thalamus. Individuals with autism frequently experience sensory processing difficulties, so defects in brain wiring between the thalamus and cortex, where sensory processing largely occurs, could be an underlying problem in some of these individuals. Consistent with the idea that autism is linked to fewer connections between neurons in the cortex and other brain regions, Cowan’s team is investigating whether EPHB2 mutations and the related brain wiring defects contribute to autism features.