1. Academic Validation
  2. De novo TBR1 mutations in sporadic autism disrupt protein functions

De novo TBR1 mutations in sporadic autism disrupt protein functions

  • Nat Commun. 2014 Sep 18;5:4954. doi: 10.1038/ncomms5954.
Pelagia Deriziotis 1 Brian J O'Roak 2 Sarah A Graham 1 Sara B Estruch 1 Danai Dimitropoulou 1 Raphael A Bernier 3 Jennifer Gerdts 3 Jay Shendure 4 Evan E Eichler 5 Simon E Fisher 6
Affiliations

Affiliations

  • 1 Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands.
  • 2 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Department of Molecular and Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, USA.
  • 3 Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, Washington 98195, USA.
  • 4 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
  • 5 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA.
  • 6 1] Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands [2] Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6525EN, The Netherlands.
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.

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