Mental retardation in autism is known to arise from a plethora of rare de novo mutations of key protein components in the synapse- the basic neuronal connection in the brain’s hardware. In a recent study published in Nature Genetics, Berkel and colleagues identified yet another de novo mutation associated with autism, which essentially consist of a series of loss of function mutations of the protein Shank2- a member of the postsynaptic scaffolding proteins located in the receiving end of synaptic connections known as the post-synaptic terminal (Berkel et al., 2010).

Scaffolding proteins function to localize key synaptic proteins and signalling molecules to the postsynaptic terminals, and are required not only for effective neurotransmission, but also spontaneous strengthening and/or pruning of synaptic connections (known as synaptic plasticity) necessary for normal cognitive development in the brain. In autism, the displacement of these crucial synaptic proteins and signalling molecules results in profound synaptic defects, and thus contribute to the delayed cognitive development and mental retardation observed in autism patients (Betancur et al., 2009).

In light of existing evidence that synaptic scaffolding proteins are mutated in cognitive disorders such as autism, the discovery of Shank2 mutations is just yet another mutation under the large list of de novo mutations associated with autism. However, unlike previous studies, Berkel and colleagues were first to use DNA microarray and sequencing technology to correlate the variations of Shank2 mutations with varying degrees or severity of mental retardation in autistic patients.

The synapse is really a hub of proteins and signalling pathways for which scientists have very little understanding. The present study by Berkel provides the first molecular scalpel to take apart and understand the workings of the brain’s synaptic hardware. Moreover, Berkel’s approach enables one to explore the elusive synaptic mechanism underlying cognitive function, literally right down to the single nucleotide level. As autism is a multi-defective disorder in various cognitive functions including language, social skills and intelligence, Berkel’s novel molecular approach paves the way to understand how these distinct cognitive functions could be linked to the complex protein components in the synapse.

References:

Berkel, S. et al. (2010). Nature Genetics. 42, 489-491.
Betancur, C. et al. (2009). Trends in Neuroscience. 32, 402-412.