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  • (Upper) Three-dimensional structure of the X. laevis Xbra T-box bound to a 24-nt DNA duplex indicating the location of residues Gly-80 (red) and Arg-237 (yellow) mutated in the missense mutations Gly80Arg, Arg237Gln, and Arg237Trp. Note that the T-box binds its target DNA (teal and blue) as a homodimer. (Lower) Human TBX5 and X. laevis Xbra T-box sequences are aligned. The Gly80Arg (R) and Arg237Gln (Q) missense mutations are located in the T-box sequence. A vertical line indicates identical sequences in Xbra and TBX5, two dots indicate functionally related residues, and one dot denotes nonconserved residues.
  • NIH

    1. 1. T Box Genes, TBX 5 and Clues about Heart and Limb Development <ul><li>T Box Genes-Background </li></ul><ul><li>TBX5-Positional Cloning </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>Heart and Limb Development </li></ul><ul><li>NHGRI/NIH November 23, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    2. 2. T Box History <ul><li>1927-Brachyury (short tail), T gene. </li></ul><ul><li>Nadine Dobrovolskaïa-Zavadskaïa-Pasteur Institute </li></ul><ul><li>http://www.informatics.jax.orggreenbook/figures/figure8-2.shtml </li></ul>
    3. 4. TBX dimers bound to DNA.. Muller and Herrmann, Nature (1997) 389:884
    4. 5. Horton etal. Dev Genes Evol (2008) 218:613
    5. 6. TBX Genes (Products) and Human Disease <ul><li>T gene Spinal Bifida </li></ul><ul><li>TBX1 DiGeorge Syndrome (CATCH 22) </li></ul><ul><li>TBX3 Ulnar Mammary Syndrome (UMS) </li></ul><ul><li>TBX4 Small patella </li></ul><ul><li>TBX5 Holt-Oram Syndrome (HOS, Heart-Hand) </li></ul><ul><li>TBX19 POMC Deficiency (TPIT) </li></ul><ul><li>TBX20 Heart Defects (septal, conduction defects) </li></ul><ul><li>TBX15 Acromegaloid facial appearance (candidate) </li></ul><ul><li>TBX21 Asthma (TBET) </li></ul><ul><li>TBX22 Cleft palate with ankyloglossia (X linked) </li></ul>
    6. 7. T Box Genes, TBX 5 and Clues about Heart and Limb Development <ul><li>T Box Genes-Background </li></ul><ul><li>TBX5-Positional Cloning </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>Heart and Limb Development </li></ul><ul><li>NHGRI/NIH November 23, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    7. 19. T Box Genes, TBX 5 and Clues about Heart and Limb Development <ul><li>T Box Genes-Background </li></ul><ul><li>TBX5-Positional Cloning </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>Heart and Limb Development </li></ul><ul><li>NHGRI/NIH November 23, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    8. 25. Fan, C. et al. J. Biol. Chem. 2003;278:8780-8785 Immunostaining of NIH-3T3 cells expressing human TBX5
    9. 26. Camarata etal. J Cell Bio (2006) 174:339
    10. 27. Kulisz and Simon, Mol Cell Bio (2008) 28:1553
    11. 29. (Upper) Three-dimensional structure of the X. laevis Xbra T-box bound to a 24-nt DNA duplex indicating the location of residues Gly-80 (red) and Arg-237 (yellow) mutated in the missense mutations Gly80Arg, Arg237Gln, and Arg237Trp Basson C. T. et.al. PNAS 1999;96:2919-2924 ©1999 by The National Academy of Sciences
    12. 30. T Box Genes, TBX 5 and Clues about Heart and Limb Development <ul><li>T Box Genes-Background </li></ul><ul><li>TBX5-Positional Cloning </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>Heart and Limb Development </li></ul><ul><li>NHGRI/NIH November 23, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    13. 32. TBX5 mutant mouse on bottom. Photo: Malcolm Logan
    14. 33. Plageman, T. F. et al. J. Biol. Chem. 2004;279:19026-19034 The T-box binding consensus sequences of the ANF promoter are required for regulation by Tbx5 and Tbx20
    15. 34. Srivastava, D. Cell. 2006 Sep 22;126(6):1037-48 .
    16. 35. http://www.nature.com/nature/journal/v459/n7247/abs/nature08039.html http://www.nature.com/nature/journal/v461/n7260/abs/nature08324.html
    17. 36. T Box Genes, TBX 5 and Clues about Heart and Limb Development <ul><li> Conclusions </li></ul><ul><li>1 Holt-Oram Syndrome caused by haploinsufficiency of TBX5 </li></ul><ul><li>2 TBX5 master regulator gene in heart septation (wall formation) and forelimb development (radial) </li></ul><ul><li>3 TBX5 involved in: Splicing mRNA, chamber formation, and induction of beating cardiomyocytes </li></ul>
    18. 37. Collaborators <ul><li>Jonathan and Christine (Cricket) Seidman </li></ul><ul><li>Craig Basson </li></ul><ul><li>Robert Lin </li></ul><ul><li>Johann Soults </li></ul><ul><li>Tatiana Levi </li></ul><ul><li>Benoit Bruneau </li></ul><ul><li>Raju Kucherlapati </li></ul><ul><li>Cynthia Morton </li></ul>
    19. 38. T Box Genes, TBX5 and Clues about Heart and Limb Development <ul><li> Thank You </li></ul><ul><li>NHGRI/NIH November 23, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    20. 41. Srivastava, D. Cell. 2006 Sep 22;126(6):1037-48 .
    21. 43. http://www.nature.com/nature/journal/v459/n7247/full/459654a.html
    22. 44. TBX 3/5-forelimbs (ulnar/radius) and TBX2/4-hindlimbs (tibia/fibia) Photo : Malcolm Logan
    23. 46. Moskowitz etal. Cell (2007) 129:1365
    24. 49. Moody, Principles of Developmental Genetics, AP Press, 2007.
    25. 51. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 3. The heart of Drosophila
    26. 52. Horton etal. Dev Genes Evol (2008) 218:613
    27. 53. Chick embryos 4 Day Gestation, in situ hybridization. The cells expressing Tbx5 will form a wing; those expressing Tbx4 will form a leg. Tbx4 and Tbx5 code for related gene regulatory proteins, which are thought to dictate which type of limb develops. H. Ohuchi et al., Development (1998)125:51–60
    28. 54. Logan, M. Development 2003;130:6401-6410 (A) Representation of the prospective limb territories in a stage 15 chick embryo
    29. 55. Rodriguez-Esteban etal, Nature (1999) 398:814
    30. 56. Horton etal., Dev Genes Evol (2008) 218:613.
    31. 69. http://www.nature.com/nature/journal/v459/n7247/abs/nature08039.html
    32. 70. Bruneau. Nature, 451:943 (2008)
    33. 71. Horton etal., Dev Genes Evol (2008) 218:613.
    34. 72. Bruneau. Nature, 451:943 (2008)
    35. 73. Bruneau. Nature, 451:94(2008)
    36. 74. Bruneau. Nature, 451:943 (2008)

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