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The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia

Nature Genetics volume 29, pages 179–183 (2001)Cite this article

Abstract

Formation of the secondary palate is a complex step during craniofacial development. Disturbance of the events affecting palatogenesis results in a failure of the palate to close. As a consequence of deformity, an affected child will have problems with feeding, speech, hearing, dentition and psychological development. Cleft palate occurs frequently, affecting approximately 1 in 1,500 births; it is usually considered a sporadic occurrence1 resulting from an interaction between genetic and environmental factors2. Although several susceptibility loci have been implicated, attempts to link genetic variation to functional effects have met with little success3. Cleft palate with ankyloglossia (CPX; MIM 303400) is inherited as a semidominant X-linked disorder previously described in several large families of different ethnic origins4,5,6,7,8,9,10,11 and has been the subject of several studies that localized the causative gene to Xq21 (refs. 10–13). Here we show that CPX is caused by mutations in the gene encoding the recently described T-box transcription factor TBX22 (ref. 14). Members of the T-box gene family are known to play essential roles in early vertebrate development, especially in mesoderm specification15. We demonstrate that TBX22 is a major gene determinant crucial to human palatogenesis. The spectrum of nonsense, splice-site, frameshift and missense mutations we have identified in this study indicates that the cleft phenotype results from a complete loss of TBX22 function.

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Figure 1: Candidate genes identified in the CPX interval in Xq21.
Figure 2: Mutation analysis in CPX families.
Figure 3: Alignment of the T-box domain from different T-box family members and different species.
Figure 4: Expression analysis of TBX22.

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References

  1. Leck, I. The geographical distribution of neural tube defects and oral clefts. Br. Med. Bull. 40, 390–395 (1984).

    Article  CAS  Google Scholar 

  2. Fraser, F.C. The genetics of cleft lip and palate: yet another look. in Current Research Trends in Prenatal Craniofacial Development (eds R.M. Pratt and K.L. Christiansen) 357–366 (National Institutes of Health, 1980).

    Google Scholar 

  3. Wilkie, A.O. & Morriss-Kay, G.M. Genetics of craniofacial development and malformation. Nature Rev. Genet. 2, 458–468 (2001).

    Article  CAS  Google Scholar 

  4. Bjornsson, A., Arnason, A. & Tippet, P. X-linked cleft palate and ankyloglossia in an Icelandic family. Cleft Palate J. 26, 3–8 (1989).

    CAS  Google Scholar 

  5. Lowry, R.B. Sex linked cleft palate in a British Columbia Indian family. Pediatrics 46, 123–128 (1970).

    CAS  Google Scholar 

  6. Rushton, A.R. Sex linked inheritance of cleft palate. Hum. Genet. 48, 179–181 (1979).

    Article  CAS  Google Scholar 

  7. Rollnick, B.R. & Kaye, C.I. Mendelian inheritance of isolated nonsyndromic cleft palate. Am. J. Med. Genet. 24, 465–473 (1986).

    Article  CAS  Google Scholar 

  8. Bixler, D. Letter to the editor: X-linked cleft palate. Am. J. Med. Genet. 28, 503–505 (1987).

    Article  CAS  Google Scholar 

  9. Hall, B.D. Letter to the editor: a further X-linked isolated nonsyndromic cleft palate family with a nonexpressing obligate affected male. Am. J. Med. Genet. 26, 239–240 (1987).

    Article  CAS  Google Scholar 

  10. Gorski, S.M., Adams, K.J., Birch, P.H., Friedman, J.M. & Goodfellow, P.J. The gene responsible for X-linked cleft palate (CPX) in a British Columbia native kindred is localized between PGK1 and DXYS1. Am. J. Hum. Genet. 50, 1129–1136 (1992).

    CAS  PubMed Central  Google Scholar 

  11. Gorski, S.M. et al. Linkage analysis of X-linked cleft palate and ankyloglossia in Manitoba Mennonite and British Columbia Native kindreds. Hum. Genet. 94, 141–148 (1994).

    Article  CAS  Google Scholar 

  12. Moore, G.E. et al. Linkage of an X-chromosome cleft palate gene. Nature 326, 91–92 (1987).

    Article  CAS  Google Scholar 

  13. Stanier, P. et al. The localization of a gene causing X-linked cleft palate and ankyloglossia (CPX) in an Icelandic kindred is between DXS326 and DXYS1X. Genomics 17, 549–555 (1993).

    Article  CAS  Google Scholar 

  14. Laugier-Anfossi, F. & Villard, L. Molecular characterization of a new human T-box gene (TBX22) located in xq21.1 encoding a protein containing a truncated T-domain. Gene 255, 289–296 (2000).

    Article  CAS  Google Scholar 

  15. Papaioannou, V.E. & Silver, L.M. The T-box gene family. BioEssays 20, 9–19 (1998).

    Article  CAS  Google Scholar 

  16. Forbes, S.A. et al. Refined mapping and YAC contig construction of the X-linked cleft palate and ankyloglossia locus (CPX) including the proximal X-Y homology breakpoint within Xq21.3. Genomics 31, 36–43 (1996).

    Article  CAS  Google Scholar 

  17. Braybrook, C. et al. Physical and transcriptional mapping of the X-linked cleft palate and ankyloglossia (CPX) critical region. Hum. Genet. 108, 537–545 (2001).

    Article  CAS  Google Scholar 

  18. Richardson, M.P., Braybrook, C., Tham, M., Moore, G.E. & Stanier, P. Molecular cloning and characterization of a highly conserved human 67k-Da laminin receptor pseudogene mapping to Xq21.3. Gene 206, 145–150 (1998).

    Article  CAS  Google Scholar 

  19. Braybrook, C. et al. Identification and characterization of KLHL4, a novel human homologue of the Drosophila kelch gene that maps within the X-linked cleft palate and ankyloglossia (CPX) critical region. Genomics 72, 128–136 (2001).

    Article  CAS  Google Scholar 

  20. Wiktop, C.J., MacCollum, D.W. & Rubin, A. Handbook of Congenital Malformations (Saunders, Philadelphia, 1967).

    Google Scholar 

  21. Prescott, N.J., Lees, M.M, Winter, R.M. & Malcolm, S. Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs. Hum. Genet. 106, 345–350 (2000).

    Article  CAS  Google Scholar 

  22. Culbertson, M.R. RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 15, 74–80 (1999).

    Article  CAS  Google Scholar 

  23. Sözen, M.A. et al. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nature Genet. 29, 141–142 (2001).

    Article  Google Scholar 

  24. Dobrovolskaia-Zavadskaia, N. Sur la mortification spontanée de la queue chez la souris nouveau-née et sur l'existence d'un caractère (facteur) héréditaire 'non-viable'. C. R. Seanc. Soc. Biol. 97, 114–116 (1927).

    Google Scholar 

  25. Wilkinson, D.G., Bhatt, S. & Herrmann, B.G. Expression pattern of the mouse T gene and its role in mesoderm formation. Nature 343, 657–659 (1990).

    Article  CAS  Google Scholar 

  26. Bamshad, M. et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nature Genet. 16, 311–315 (1997).

    Article  CAS  Google Scholar 

  27. Basson, C.T. et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nature Genet. 15, 30–35 (1997).

    Article  CAS  Google Scholar 

  28. Jerome, L.A. & Papaioannou, V.E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).

    Article  CAS  Google Scholar 

  29. Lindsay, E.A. et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).

    Article  CAS  Google Scholar 

  30. Tada, M. & Smith, J.C. T-targets: clues to understanding the functions of T-box proteins. Dev. Growth Differ. 43, 1–11 (2001).

    Article  CAS  Google Scholar 

  31. Proetzel, G. et al. Transforming growth factor–β 3 is required for secondary palate fusion. Nature Genet. 11, 409–414 (1995).

    Article  CAS  Google Scholar 

  32. Wakeling, E.L., Abu-Amero, S.N., Stanier, P., Preece, M.A. & Moore, G.E. Human EGFR, a candidate for the Silver-Russell syndrome, is biallelically expressed in a wide range of fetal tissues. Eur. J. Hum. Genet. 6, 158–164 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We wish to thank R. Williamson, O. Jensson, C. Greenberg, J. Freidman, A. Ivens, S. Forbes, M. Richardson, M. Tham, V. Mandryko, L. Bentley, M.T. Ross and members of the Sanger Centre Human X Chromosome Project Team for their invaluable contributions to this study; A. Davies and S. Bayliss for DNA sequencing; the families and patients studied for their participation; and M. Parker and A.J. Copp for critical reading of the manuscript. This work was supported by the Birth Defects Foundation United Kingdom, the Dunhill Medical Trust, the Medical Research Council, the Icelandic Research Council and the Hayward Foundation.

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Authors and Affiliations

  1. Institute of Reproductive and Developmental Biology, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

    Claire Braybrook, Kit Doudney, Gudrun E. Moore & Philip Stanier

  2. Departamento de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, São Paulo, Brazil

    Ana Carolina B. Marçano

  3. The Bloodbank, 101 Reykjavik, Iceland

    Alfred Arnason

  4. Department of Plastic Surgery, The University Hospital, 101 Reykjavik, Iceland

    Arni Bjornsson

  5. Medical Genetics Unit, St George's Hospital Medical School, Tooting, London, UK

    Michael A. Patton

  6. Departments of Surgery, Genetics, and Obstetrics & Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA

    Paul J. Goodfellow

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  1. Claire Braybrook
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Correspondence to Philip Stanier.

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Braybrook, C., Doudney, K., Marçano, A. et al. The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. Nat Genet 29, 179–183 (2001). https://doi.org/10.1038/ng730

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