title: De novo TBR1 mutations in sporadic autism disrupt protein functions.
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.
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands.
authors.forename: Pelagia
authors.initials: P
authors.lastname: Deriziotis
authors.affiliation: 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.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Graham
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands.
authors.forename: Sara B
authors.initials: SB
authors.lastname: Estruch
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands.
authors.forename: Danai
authors.initials: D
authors.lastname: Dimitropoulou
authors.affiliation: Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Bernier
authors.affiliation: Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gerdts
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: 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.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
mesh_terms: D000595:Amino Acid Sequence; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019281:Dimerization; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007806:Language Disorders / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D025941:Protein Interaction Mapping; D017386:Sequence Homology, Amino Acid; D020825:T-Box Domain Proteins / Q000235:genetics*; D020798:Two-Hybrid System Techniques
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D020825:T-Box Domain Proteins; C574705:TBR1 protein, human