De novo TBR1 mutations in sporadic autism disrupt protein functions

Pelagia Deriziotis, Brian J. O’Roak, Sarah A. Graham, Sara B. Estruch, Danai Dimitropoulou, Raphael A. Bernier, Jennifer Gerdts, Jay Shendure, Evan E. Eichler and Simon E. Fisher ()
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Pelagia Deriziotis: Max Planck Institute for Psycholinguistics
Brian J. O’Roak: University of Washington School of Medicine
Sarah A. Graham: Max Planck Institute for Psycholinguistics
Sara B. Estruch: Max Planck Institute for Psycholinguistics
Danai Dimitropoulou: Max Planck Institute for Psycholinguistics
Raphael A. Bernier: University of Washington
Jennifer Gerdts: University of Washington
Jay Shendure: University of Washington School of Medicine
Evan E. Eichler: University of Washington School of Medicine
Simon E. Fisher: Max Planck Institute for Psycholinguistics

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

Date: 2014
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DOI: 10.1038/ncomms5954

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