Nature Genetics
16, 311 - 315 (1997)
doi:10.1038/ng0797-311
Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndromeMichael Bamshad1, 10, *, Robert C. Lin2, *, David J. Law3, W. Scott Watkins4, Patrycja A. Krakowiak4, Mary E. Moore4, Piergiorgio Franceschini5, Roberto Lala6, Lewis B. Holmes7, Tom C. Gebuhr3, Benoit G. Bruneau2, Albert Schinzel8, J. G. Seidman2, Christine E. Seidman9
& Lynn B. Jorde4, 6
1Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah 84112, USA.
2Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
3Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
4Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah 84112, USA.
5Istituto di Discipline Pediatriche, Servizio di Genetica Clinica, Universita di Torino, Torino, Italy.
6Divisione di Endrocrinologia Pediatrica, Ospedale Infantile R. Margherita, Torino, Italy.
7Genetics and Teratology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
8Institute of Medical Genetics, University of Zurich, Raemistrasse 74, CH-8001, Zurich, Switzerland.
9Howard Hughes Medical Institute and Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
10Correspondence should be addressed to M.B.
*M.B. and R.C.I. contributed equally to this work. 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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