Abstract
Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity1. Although studies of twins consistently indicate that a significant genetic component is involved1,2,3, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait4. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval6. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.
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Acknowledgements
We are deeply indebted to the KE family whose continued cooperation has made this research possible. We also thank CS and family for agreeing to participate in this study. We thank D. C. Jamison and E. D. Green for facilitating completion of the 7q31 genomic sequence; M. Fox, S. Jeremiah and S. Povey for the chromosome 7 hybrids; E. R. Levy for assistance with cytogenetic analyses; D. I. Stuart, E. Y. Jones and R. M. Esnouf for advice on structural analyses of forkhead domains; L. Rampoldi for assistance with northern blots; and E. Dunne for help with sequence analyses of other 7q31 candidate genes. Chromosome 7 sequence data were generated by the Washington University Genome Sequencing Center. This study was funded by the Wellcome Trust. A.P.M. is a Wellcome Trust Principal Research Fellow.
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Figure S1
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Northern blot analyses of adult and foetal tissues with a probe containing exons 8-11 of FOXP2 reveals a transcript of ~6.5kb. Results from the control probe beta-actin are also shown. Tissues analysed were heart (H), brain (B), placenta (Pl), lung (Lu), liver (Li), skeletal muscle (S), kidney (K) and pancreas (Pa). The difference between the size of the transcript observed here and that of the open reading frame (2.1kb) indicates the presence of large 5’ and/or 3’ untranslated regions that may be involved in regulating expression of the gene.
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Lai, C., Fisher, S., Hurst, J. et al. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519–523 (2001). https://doi.org/10.1038/35097076
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DOI: https://doi.org/10.1038/35097076
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