Abstract
Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human T8X3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.
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References
Leck, I. in Human Malformations and Related Anomalies. Vol.1 (eds. Stevenson, R.E., Hall, J.G. & Goodman, M.M.) 65–94 (Oxford University Press, Oxford, 1993).
Muragaki, Y., Mundlos, S., Upton, J. & Olson, B.R. Altered growth and branching patterns in synpolydactyly caused by mutations in HoxD13. Science. 272, 548–551 (1996).
Thomas, J.T. et al. A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Nature Genet. 12, 315–317 (1996).
Pallister, P.D., Herrmann, J. & Opitz, J.M. A pleiotropic dominant mutation affecting skeletal, sexual and apocrine-mammary development. Birth Defects Orig. Art. Ser. 12, 247–254 (1976).
Gonzales, C.H., Herrmann, J. & Opitz, J.M. Mother and son affected with the ulnar-mammary syndrome type Pallister. Eur. J. Pediatr. 123, 225–235 (1976).
Hecht, J.T. & Scott, C.I. Jr., The Schinzel syndrome in a mother and daughter. Clin. Genet. 25, 63–67 (1984).
Schinzel, A. Ulnar-mammary syndrome. J. Med. Genet. 24, 778–781 (1987).
Schinzel, A., Illig, R. & Prader, A. The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin. Genet. 32, 160–168 (1987). Erratum. Clin. Genet. 32, 425 (1987).
Franceschini, P. et al. Possible relationship between ulnar-mammary syndrome and split hand with aplasia of the ulna syndrome. Am. J. Med. Genet. 44, 807–812 (1992).
Bamshad, M., Root, S. & Carey, J.C. Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome. Am.J. Med. Genet. 65, 325–331 (1996).
Bamshad, M. et al. A gene for ulnar-mammary syndrome maps to 12q23-q24.1. Hum. Molec. Genet. 4, 1973–1977 (1995).
Bollag, R.J. et al. An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T-locus. Nature Genet. 7, 383–389 (1994).
Herrmann, B.G. & Kispert, A. The T genes in embryogenesis. Trends Genet. 10, 280–286 (1994).
Kispert, A., Koschorz, B. & Herrmann, B.G. The T protein encoded by Brachyury is a tissue-specific transcription factor. EMBO J. 14, 4763–4772 (1995).
Gibson-Brown, J.J. et al. Evidence of a role for T-box genes in the evolution of limb morphogenesis and the specification of forelimb/hindlimb indentity. Mech. Dev. 56, 93–101 (1996).
Chapman, D.L. et al. Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev. Dyn. 206, 379–390 (1996).
Basson, C.T. et al. Mutations in human TBX5cause limb and cardiac malformation in Holt-Oram syndrome. Nature Genet. 15, 30–35 (1997).
Law, D.J., Gebuhr, T., 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).
Li, Q.Y. et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nature Genet. 15, 21–29 (1997).
Agulnik, S.I. et al. Evolution of mouse T-box genes by tandem duplication and cluster dispersion. Genetics. 144, 249–254 (1996).
Herrmann, B.C., Labeit, S., Poustka, A., King, T. & Lehrach, H. Cloning of the T gene required in mesoderm formation in the mouse. Nature 343, 617–622 (1990).
Smith, J.C., Price, B.M., Green, J.B.A., Weigel, D. & Herrmann, B.G. Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell 67, 79–87 (1991).
Pflugfelder, G.O., Roth, H. & Poeck, B. A homology domain shared between Drosophila optomotor-blind, and mouse Brachyury is involved in DNA binding. Biochem. Biophys. Res. Comm. 186, 918–925 (1992).
Schulte-Merker, S., van Eeden, F.J., Halpern, M.E., Kimmel, C.B., & Nusslein-Volhard, C. No tail (ntl) is the zebrafish homologue of the mouse T (Brachyury) gene. Development 120, 1009–1015 (1994).
Kispert, A., Herrmann, B.C., Leptin, M. & Reuter, R. Homologs of the mouse Brachyury gene are involved in the specification of posterior terminal structures in Drosophila, Tribolium, and Locusta. Genes Dev. 8, 2137–2150 (1994).
Agulnik, S.I., Bollag, R.J. & Silver, L.M. Conservation of the T-box gene family from M. musculusto C. elegans. Genomics 25, 214–219 (1995).
Bulfone, A. et al. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15, 63–78 (1995).
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).
Morrison, K. et al. Genetic mapping of the human homologue (T) of mouse T (Brachyury) and a search for allele association between human 7and spina bifida. Hum. Mol. Genet. 5, 669–674 (1996).
Nakatani, Y., Yasuo, H., Satoh, N. & Nishida, H. Basic fibroblast growth factor induces notochord formation and the expression of As-T, a Brachyury homolog, during ascidian embryogenesis. Development 122, 2023–2031 (1996).
Chapman, D.L., Agulnik, I., Hancock, S., Silver, L.M. & Papaioannou, V.E. Tbx6, a mouse T-box gene implicated in paraxial mesoderm formation at gastrulation. Dev. Biol. 180, 534–542 (1996).
Holt, M. & Oram, S. Familial heart disease and skeletal manifestations. Br. Heart J. 22, 236–242 (1960).
Basson, C.T. et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N. Engl. J. Med. 330, 885–891 (1994).
Rudiger, R.A., Haase, W. & Passarge, E. Association of ectrodactyly, ectodermal dysplasia and cleft lip-palate: the EEC syndrome. Am. J. Dis. Child. 120, 160–163 (1970).
Buss, P.W., Hughes, H.E. & Clarke, A. Twenty-four cases of the EEC syndrome: clinical presentation and management. J. Med. Genet. 32, 716–723 (1995).
Hamel, B. et al. A large family with limb-mammary syndrome: clinical and molecular findings. Eur. J. Hum. Genet. 4, Suppl. 1, 148 (1996).
Bell, G.I., Karem, J.H. & Rutter, J.R. Polymorphic DNA region adjacent to the 5′ end of the human insulin gene. Proc. Natl. Acad. Sci. USA. 78, 5759–5763 (1981).
Anderson, M.A. & Gusella, J.F. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro Cell. Dev. Biol. 20, 856–858 (1984).
Thierfelder, L. et al. α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 77, 701–712 (1994).
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Bamshad, M., Lin, R., Law, D. et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16, 311–315 (1997). https://doi.org/10.1038/ng0797-311
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DOI: https://doi.org/10.1038/ng0797-311
