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Mutations in human cause limb and cardiac malformation in Holt-Oram syndrome

An Erratum to this article was published on 01 April 1997

Abstract

Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects. Here, we demonstrate that mutations in the human TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family. A nonsense mutation in TBX5 causes Holt-Oram syndrome in affected members of one family; a TBX5 missense mutation was identified in affected members of another. We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome.

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References

  1. Olson, E.N. & Srivastava, D. Molecular pathways controlling heart development. Science 272, 671–676 (1996).

    Article  CAS  Google Scholar 

  2. Park, M., Wu, X., Golden, K., Axelrod, J.D. & Bodmer, R. The wingless signaling pathway is directly involved in Drosophila heart development. Develop. Biol. 177, 104–116 (1996).

    Article  CAS  Google Scholar 

  3. Levin, M., Johnson, R.L., Stern, C.D., Kuehn, M. & Tabin, C. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82, 803–814 (1995).

    Article  CAS  Google Scholar 

  4. Rossant, J. Mouse mutants and cardiac development. Circ. Res. 78, 349–353 (1996).

    Article  CAS  Google Scholar 

  5. Huang, J.X., Potts, J.D., Vincent, E.B., Weeks, D.L. & Runyan, R.B. Mechanisms of cell transformation in the embryonic heart. Ann. NY Acad. Sci. 752, 217–330 (1995).

    Article  Google Scholar 

  6. D'Alton, M.E. & DeCherney, A.M. Prenatal diagnosis. New Engl. J.Med. 328, 114–120 (1993).

    Article  CAS  Google Scholar 

  7. Basson, C.T. . et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). New Engl. J. Med. 330, 885–891 (1994).

    Article  CAS  Google Scholar 

  8. Holt, M. & Oram, S. Familial heart disease with skeletal malformations. Br. Heart J. 22, 236–242 (1960).

    Article  CAS  Google Scholar 

  9. Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 142900:9/7/96. World Wide Web URL:. http://www3.ncbi.nlm.nih.gov/omim/.

  10. Gall, J.C., Stern, A.M., Cohen, M.M., Adams, M.S. & Davidson, R.T. (1966). Holt-Oram syndrome: clinical and genetic study of a large family. Am. J. Hum. Genet. 18, 187–200 (1966).

    PubMed  PubMed Central  Google Scholar 

  11. Hurst, J.A., Hall, C.M. & Baraitser, M., Holt-Oram syndrome. J. Med. Genet. 28, 406–410 (1991).

    Article  CAS  Google Scholar 

  12. Kullman, F. & Grimm, T., h. med. Wochenschr. 118, 1455–1462 (1993).

    Article  Google Scholar 

  13. Letts, R.M., Chudley, A.E., Cumming, G. & Shokier, M.H. The upper limb-cardiovascular syndrome (Holt-Oram syndrome). Clin. Orthop. Relat Res. 116, 149–154 (1976).

    Google Scholar 

  14. Pruznanski, W. Familial congenital malformations of the heart and upper limbs. A syndrome of Holt-Oram. Cardiologia 45, 1–38 (1964).

    Google Scholar 

  15. Ruzic, B., Bosnar, B. & Beleznay, O. Ein seltener herzfehler als symptom des Holt-Oram-Syndroms. Radiologe 21, 296–299 (1981).

    CAS  PubMed  Google Scholar 

  16. Sahn, D.J., Goldberg, S.J., Alien, H.D. & Canale, J.M. Cross-sectional echocardiographic imaging of supracardiac total anomalous pulmonary venous drainage to a vertical vein in a patient with Holt-Oram syndrome. Chest 79, 113–115 (1981).

    Article  CAS  Google Scholar 

  17. Smith, A.T., Sack, G.H. & Taylor, G.J. Holt-Oram syndrome. J. Pediatr. 95, 538–543 (1979).

    Article  CAS  Google Scholar 

  18. Starke, H., Schimke, R.N. & Dunn, M. Upper-limb cardiovascular syndrome. Am. J. Cardio. 19, 588–592 (1967).

    Article  CAS  Google Scholar 

  19. Zhang, K.Z., Sun, Q.B. & Cheng, T.O. Holt-Oram syndrome in China: a collective review of 18 cases. Am. Heart J. 111, 572–577 (1986).

    Article  CAS  Google Scholar 

  20. Basson, C.T. et al. Genetic heterogeneity of heart-hand syndromes. Circulation 91, 1326–1329 (1995).

    Article  CAS  Google Scholar 

  21. Bonnet, D. et al.A gene for Holt-Oram syndrome maps to the distal long arm of chromosome 12. Nature Genet. 6, 405–408 (1994).

    Article  CAS  Google Scholar 

  22. Terrett, J.A. . et al. Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q. Nature Genet. 6, 401–404 (1994).

    Article  CAS  Google Scholar 

  23. LeBlanc-Straceski, J.M. . et al. Twenty-one polymorphic markers from human chromosome 12 for integration of genetic and physical maps. Genomics 19, 341–349 (1994).

    Article  CAS  Google Scholar 

  24. Foote, S. Construction of YAC libraries with large inserts in Current Protocols in Human Genetics (Eds Dracopoli, N. C. et al.) 5.2.2–5.2.20 (John Wiley and Sons,New York 1996).

    Google Scholar 

  25. Sternberg, N. & Shepherd, N.S. Construction of P1 bacteriophage libraries with large inserts in Current Protocols in Human Genetics (eds Dracopoli, N. C.) 5.3.1–5.3.26 (John Wiley and Sons, New York, 1996).

    Google Scholar 

  26. Buckler, A.J. . et al.Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. Natl. Acad. Sci. USA 88, 4005–1009 (1991).

    Article  CAS  Google Scholar 

  27. GDB (TM) Genome Database [database online].Baltimore (Maryland, USA): Johns Hopkins University, 1990-. Updated daily, [cited 29 April 1996]. GDB Data Type: Linkage map. Accession ID: gdb:1217496. Available from Internet: <URL:http://gdbwww.gdb.org/>.

  28. Agulnik, S.I. . et al. Evolution of Mouse T-box genes by tandem duplication and cluster dispersion. Genetics 144, 249–254 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bollag, R.J. et al. An ancient family of embryonically expressed genes sharing a conserved protein motif with the T locus. Nature Genet. 7, 383–389 (1994).

    Article  CAS  Google Scholar 

  30. Bulfone, A. . et al.T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains with the cerebral cortex. Neuron 15, 63–78 (1995).

    Article  CAS  Google Scholar 

  31. Campbell, C., Goodrich, K., Casey, G. & Beatty, B. Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. Genomics 28,255–260 (1995).

    Article  CAS  Google Scholar 

  32. Edwards, Y.H. et al. The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27. Genome Res. 6, 226–233 (1996).

    Article  CAS  Google Scholar 

  33. Herrmann, B.G. & Kispert, A. The T genes in embryogenesis. Trends Genet. 10, 280–286 (1994).

    Article  CAS  Google Scholar 

  34. Kispert, A., & Herrmann, B.G. The T protein encoded by Brachyury is a tissue-specific transcription factor. EMBO J. 14, 4763–4772 (1995).

    Article  CAS  Google Scholar 

  35. Law, D.J., Garvey, N., Agulnik, S.I. & Silver, L.M. Identification, characterization and localization to chromosome 17q21–22 of the human TBX2 homolog, member of a conserved developmental gene family. Mamm. Genome 6, 793–797 (1995).

    Article  CAS  Google Scholar 

  36. Kozak, M. Interpreting cDNA sequences: some insights from, studies on translation. Mamm. Genome 7, 563–574 (1996).

    Article  CAS  Google Scholar 

  37. Grimm, S. & Pflugfelder, G.O. Control of the gene optomotor-blind in Drosophila wing development by decapentaplegic and wingless. Science 271, 1601–1604 (1996).

    Article  CAS  Google Scholar 

  38. Satoh, N. & Jeffery, W.R. Chasing tails in ascidians: developmental insights into the origin and evolution of chordates. Trends Genet. 11, 354–359 (1995).

    Article  CAS  Google Scholar 

  39. Terrett, J.A. et al. Atranslocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene. Am. J. Hum. Genet. 59, 1337–1342 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Chapman, D.L. et al. Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Devlop. Dyn. 206, 379–390 (1996).

    Article  CAS  Google Scholar 

  41. Gibson-Brown, J.J. et al. Evidence of a role for T-box genes in the evolution of limb morphogenesis and specification of forelimb/hindlimb identity. Mech. Develop. 56, 93–101 (1996).

    Article  CAS  Google Scholar 

  42. Cohn, M.J. & Tickle, C. Limbs: a model for pattern formation within the vertebrate body plan. Trends Genet. 12, 253–257 (1996).

    Article  CAS  Google Scholar 

  43. Lawrence, P.A. & Struhl, G., Morphogens, compartments and pattern: lessons from Drosophila. Cell. 85, 951–961 (1996).

    Article  CAS  Google Scholar 

  44. Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a DPP morphogen gradient. Cell 85, 357–368 (1996).

    Article  CAS  Google Scholar 

  45. Ott, J. A computer program for linkage analysis of general human pedigrees. Am. J. Hum. Genet. 28, 528–529 (1967).

    Google Scholar 

  46. Wesley, C.S., Meyers, M.P. & Young, M.W. Rapid sequential walking from termini of cosmid, P1 and YAC inserts. Nucl. Acids Res. 22, 538–539 (1993).

    Article  Google Scholar 

  47. Thierfelder, L., et al. α-Troposmyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77, 701–712 (1994).

    Article  Google Scholar 

Download references

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Basson, C., Bachinsky, D., Lin, R. et al. Mutations in human cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15, 30–35 (1997). https://doi.org/10.1038/ng0197-30

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