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Abstract:
Autism spectrum disorders (ASD) comprise a range of neurodevelopmental syndromes characterized by extensive abnormalities of social interactions and communication, including language impairment and stereotyped behaviours. ASD aetiology has a strong genetic basis, but in most cases the specific molecular risk factors remain unknown. Recent sequencing of exomes in 20 parent-child trios with idiopathic autism uncovered 21 de novo mutations, 11 of which were protein-altering. One involved a single base insertion in FOXP1, introducing a frameshift and premature stop codon (A339SfsX4), in a severely affected ASD proband with regression and language delay. This is of particular interest since FOXP1 belongs to the same group of transcription factors as FOXP2, a gene implicated in rare monogenic speech and language disorders. The proteins encoded by FOXP1 and FOXP2 can directly interact with each other, with the potential to co-regulate downstream targets in neural circuits where they are co-expressed, including those involved in language function. Analyses of proband-derived lymphoblasts indicated that the majority of FOXP1-A339SfsX4 transcripts undergo nonsense-mediated RNA decay. Moreover, in functional cell-based assays we found that transcripts which escape this process yield a truncated protein that is mislocalised from the nucleus to the cytoplasm. Intriguingly, in addition to the FOXP1-A339SfsX4 mutation, this same ASD proband also carries a rare inherited missense variant of CNTNAP2, a gene that has been independently associated with ASD and common language impairments. We found that wildtype FOXP1 protein (like FOXP2) acts as a repressor of CNTNAP2 expression, while the truncated FOXP1 mutant protein leads to misregulation of this downstream target. Overall the functional data suggest that the FOXP1 mutation may amplify deleterious effects of the CNTNAP2 variant in the proband, consistent with a multi-hit model for disease risk. Building on this work, we have now performed similar functional characterisations for novel risk variants identified in targeted high-throughput sequencing of FOXP1 and FOXP2 in a large cohort of 1700 idiopathic ASD cases. Our findings demonstrate how the coupling of next generation sequencing with functional genomic assays can shed important new light on pathways underlying complex neurodevelopmental phenotypes like autism and language impairment.
