Abstract
BackgroundHeterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain.MethodsWe performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder.ResultsWe confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder.ConclusionsOur findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9177-2) contains supplementary material, which is available to authorized users.
Highlights
Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment
To address the possibility that FOXP2 disruption might be a factor in other disorders characterized by speech/language problems, similar screens have been performed in individuals with specific language impairment, speech sound disorder, autism, schizophrenia, and epilepsy of the speech cortex [10,11,12,13,14,15,16,17,18]
Rare FOXP2 variants implicated in neurodevelopmental disorder We examined seven rare FOXP2 variants that have been observed in individuals with neurodevelopmental disorders, including five missense variants, one stop-gain variant, and one frameshift variant (Table 1, Fig. 1a)
Summary
Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. Heterozygous disruptions of the FOXP2 gene cause a rare and severe speech and language disorder (OMIM 602081) [3]. This disorder was first reported in a three-generation. Screening of the FOXP2 coding region for proteinaltering variants has been performed in a few small cohorts of children with speech articulation disorders similar to those reported in the KE family [7,8,9]. The contribution of individual rare variants to disorder often remains unclear because the genetic evidence in isolation is insufficient to confirm a causal or contributory role, and the effect of the variant on protein function is unknown
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