Traduction: G.M.
Nat Commun. 2014 Sep 18;5:4954. doi: 10.1038/ncomms5954.
Des mutations de novo TBR1 dans l'autisme sporadique perturbent les fonctions des protéines
Deriziotis P1, O'Roak BJ2, Graham SA1, Estruch SB1, Dimitropoulou D1, Bernier RA3, Gerdts J3, Shendure J4, Eichler EE5, Fisher SE6.
Author information
- 1Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525XD, The Netherlands.
- 21] 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.
- 3Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, Washington 98195, USA.
- 4Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
- 51] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA.
- 61] 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.
Le séquençage de nouvelle génération a récemment révélé que les mutations perturbatrices récurrentes dans quelques gènes peuvent représenter 1% des cas d'autisme sporadiques. Le couplage de ces données génétiques originales aux tests empiriques de la fonction de la protéine peut éclairer les réseaux moléculaires essentiels.
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.
Ces résultats soutiennent l'hypothèse que les mutations de novo dans l'autisme sporadique ont des conséquences fonctionnelles graves. En outre, ils mettent en évidence les mécanismes neurogénétiques qui font le lien entre les différents troubles neurodéveloppementaux impliquant des troubles du langage.
Le séquençage de nouvelle génération a récemment révélé que les mutations perturbatrices récurrentes dans quelques gènes peuvent représenter 1% des cas d'autisme sporadiques. Le couplage de ces données génétiques originales aux tests empiriques de la fonction de la protéine peut éclairer les réseaux moléculaires essentiels.
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.
Ces résultats soutiennent l'hypothèse que les mutations de novo dans l'autisme sporadique ont des conséquences fonctionnelles graves. En outre, ils mettent en évidence les mécanismes neurogénétiques qui font le lien entre les différents troubles neurodéveloppementaux impliquant des troubles du langage.
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