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A forkhead-domain gene is mutated in a severe speech and language disorder

Nature volume 413, pages 519–523 (2001)Cite this article

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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Figure 1: Pedigree of the KE family.
Figure 2: Identification of the human FOXP2 gene.
Figure 3: Disruption of FOXP2 in patients with severe speech and language disorder.
Figure 4: Forkhead domains of the three known FOXP proteins aligned with representative proteins from several branches of the FOX family.

References

  1. Bishop, D. V. M., North, T. & Donlan, C. Genetic basis for specific language impairment: evidence from a twin study. Dev. Med. Child Neurol. 37, 56–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Tomblin, J. B. & Buckwalter, P. R. Heritability of poor language achievement among twins. J. Speech Lang. Hear. Res. 41, 188–199 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Dale, P. S. et al. Genetic influence on language delay in two-year-old children. Nature Neurosci. 1, 324–328 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Hurst, J. A., Baraitser, M., Auger, E., Graham, F. & Norell, S. An extended family with a dominantly inherited speech disorder. Dev. Med. Child Neurol. 32, 347–355 (1990).

    Google Scholar 

  5. Fisher, S. E., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembrey, M. E. Localization of a gene implicated in a severe speech and language disorder. Nature Genet. 18, 168–170 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Lai, C. S. L. et al. The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am. J. Hum. Genet. 67, 357–368 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gopnik, M. & Crago, M. B. Familial aggregation of a developmental language disorder. Cognition 39, 1–50 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Vargha-Khadem, F., Watkins, K., Alcock, K., Fletcher, P. & Passingham, R. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc. Natl Acad. Sci. USA 92, 930–933 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vargha-Khadem, F. et al. Neural basis of an inherited speech and language disorder. Proc. Natl Acad. Sci. USA 95, 12695–12700 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Margolis, R. L. et al. cDNAs with long CAG trinucleotide repeats from human brain. Hum. Genet. 100, 114–122 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Lai, E., Clark, K. L., Burley, S. K. & Darnell, J. E. Jr Hepatocyte nuclear factor 3/fork head or “winged helix” proteins: a family of transcription factors of diverse biologic function. Proc. Natl Acad. Sci. USA 90, 10421–10423 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li, C. & Tucker, P. W. DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain. Proc. Natl Acad. Sci. USA 90, 11583–11587 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kaufmann, E. & Knöchel, W. Five years on the wings of fork head. Mech. Dev. 57, 3–20 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Kaestner, K. H., Knöchel, W. & Martinez, D. E. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 14, 142–146 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Shu, W., Yang, H., Zhang, L., Lu, M. M. & Morrisey, E. E. Characterization of a new subfamily of winged-helix/forkhead (fox) genes that are expressed in the lung and act as transcriptional repressors. J. Biol. Chem. 276, 27488–27497 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Clark, K. L., Halay, E. D., Lai, E. & Burley, S. K. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412–420 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Nishimura, D. Y. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genet. 19, 140–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Mears, A. J. et al. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld–Rieger anomaly. Am. J. Hum. Genet. 63, 1316–1328 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Clifton-Bligh, R. J. et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nature Genet. 19, 399–401 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Fang, J. et al. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema–distichiasis syndrome. Am. J. Hum. Genet. 67, 1382–1388 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Crisponi, L. et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nature Genet. 27, 159–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Semina, E. V., Brownell, I., Mintz-Hittner, H. A., Murray, J. C. & Jamrich, M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum. Mol. Genet. 10, 231–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. De Felice, M. et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nature Genet. 19, 395–398 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Smith, R. S. et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum. Mol. Genet. 9, 1021–1032 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Lehmann, O. J. et al. Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am. J. Hum. Genet. 67, 1129–1135 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nishimura, D. Y. et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am. J. Hum. Genet. 68, 364–372 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cummings, C. J. & Zoghbi, H. Y. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum. Mol. Genet. 9, 909–916 (2000).

    Article  CAS  PubMed  Google Scholar 

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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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Author notes

  1. Cecilia S. L. Lai, Simon E. Fisher and Jane A. Hurst: These authors contributed equally to this work

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Cecilia S. L. Lai, Simon E. Fisher & Anthony P. Monaco

  2. Department of Clinical Genetics, Oxford Radcliffe Hospital, Oxford, OX3 7LJ, UK

    Faraneh Vargha-Khadem

  3. Developmental Cognitive Neuroscience Unit, Institute of Child Health, Mecklenburgh Square, London, WC1N 2AP, UK

    Cecilia S. L. Lai & Simon E. Fisher

Authors
  1. Cecilia S. L. Lai
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  2. Simon E. Fisher
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  3. Jane A. Hurst
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  4. Faraneh Vargha-Khadem
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  5. Anthony P. Monaco
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Corresponding author

Correspondence to Anthony P. Monaco.

Supplementary information

Figure S1

(JPG 10.6 KB)

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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