Editors' ChoiceAutism


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Science Translational Medicine  21 Jan 2015:
Vol. 7, Issue 271, pp. 271ec10
DOI: 10.1126/scitranslmed.aaa5545

We live in an era of unfolding genome complexity. In a single cell, the tightly coiled DNA contains not only coding sequences (exons), but also long noncoding sequences or very short sequences that encode a few amino acids (microexons). Irimia et al. have now developed an algorithm that allowed them to detect hundreds of novel microexons, some of which may encode just a single amino acid. These microexons showed a marked degree of conservation among vertebrates. Moreover, a large fraction of these conserved small DNA elements were specifically and dynamically regulated during the late stages of neuron maturation, indicating their potential functional importance during brain development.

The authors showed that inclusion of these microexons in the final RNA product contributed to the function of numerous neuronal proteins. Microexons have the ability to change the surface structure of proteins in ways that longer exons cannot. Using luminescence-based mammalian interactome mapping in human cell lines, the authors showed that the insertion of selected neuronal microexons enhanced interactions between proteins, whereas the deletion of microexons caused the loss of these protein-protein interactions. Subsequent screening of several known splicing regulators identified nSR100 as a potent regulator of neuronal microexon inclusion. Moreover, the authors found that many of the identified neuronal microexons were frequently misregulated in the brains of humans suffering from autism spectrum disorders, who also displayed reduced expression of nSR100. These data suggest that erroneous exclusion of microexons through mis-splicing may contribute to neurodevelopmental diseases including autism.

The discovery of microexons will open up a new line of research into the causes of autism and other neurological disorders. The work is likely to lead to the discovery of more microexons with myriad roles in different cellular processes. A potential macro-benefit of these microexons may be to boost our understanding of the pathogenic mechanisms underlying a variety of neurological diseases.

M. Irimia et al., A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159, 1511–1523 (2014). [PubMed]

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