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.

Insights into the Genetic Foundations of Human Communication

“…The language deficits in the distinct disorders caused by disruptions in FOXP1, TBR1 and FOXP2 may relate to dysregulation of common downstream targets as a result of loss of protein-protein interactions. This hypothesis is supported by the fact that pathogenic mutations that disrupt the TBR1 protein result in loss of interaction with FOXP2 (Deriziotis et al 2014). …”

“…Therefore, in addition to the situation where one phenotype corresponds to many genotypes, we can also expect that one genotype corresponds to multiple phenotypes. Table 2 outlines the range of experimental paradigms that have been applied to molecular studies of developmental communication disorders to tackle their heterogeneous genetic architecture and make best use of available resources (Newbury and Monaco 2010;Kang and Drayna 2011;Deriziotis and Fisher 2013;Newbury et al 2014). This research field is at a relatively early stage of development and studies need (when possible) to take an unbiased genomewide approach to gene-hunting.…”

“…Microarray technology and next-generation sequencing permit the rapid acquisition of comprehensive genetic information from large numbers of individuals, but the interpretation of these data in relation to language phenotypes remains challenging (Deriziotis and Fisher 2013;Cooper and Shendure 2011). Given that we know little about the relevant biology at this point, one difficulty is the lack of clear a priori candidate genes.…”

“…Such work is important to avoid misattributing a causal role to a variant just because it occurs in a well-known protein (Guidugli et al 2014). It remains extremely difficult to judge the importance of non-coding variants that are identified in genomic screening (Deriziotis and Fisher 2013;Cooper and Shendure 2011). Non-coding DNA makes up over 98 % of the genome and generally harbors more variation than coding DNA because it is not under such strong purifying selection, although around 3-4 % of non-coding DNA is highly conserved and shows evidence of selection, suggesting that these regions may have conserved roles in regulating gene expression.…”

“…New monogenic ID and ASD syndromes are continuously being discovered, and some of these reveal specific molecular links between ID/ ASD and more language-specific disorders. Two recentlydiscovered syndromes are caused by haploinsufficiency of transcription factors that are known to directly interact with FOXP2 (Li et al 2004;Sakai et al 2011;Deriziotis et al 2014). One syndrome results from mutations of FOXP1, a paralog of FOXP2 which shows partially overlapping expression in brain regions including the striatum (Ferland et al 2003).…”