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Molecular and Cellular Biology, October 1998, p. 6044-6051, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Haploinsufficiency of MSX1: a Mechanism for Selective Tooth Agenesis

Gezhi Hu,^1,2 Heleni Vastardis,^3,4,5, Andrew J. Bendall,^1,2 Zhaoqing Wang,^1,2 Malcolm Logan,⁴ Hailan Zhang,^1,2, Craig Nelson,^4,§ Stacey Stein,^1,2 Norma Greenfield,² Christine E. Seidman,^3,6 J. G. Seidman,^3,4 and Cory Abate-Shen^1,2,*

Center for Advanced Biotechnology and Medicine¹ and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson School of Medicine,² Piscataway, New Jersey 08854, and Howard Hughes Medical Institute³ and Department of Genetics,⁴ Harvard Medical School, Department of Orthodontics, Harvard School of Dental Medicine,⁵ and Howard Hughes Medical Institute, Division of Cardiology, Brigham and Women's Hospital,⁶ Boston, Massachusetts 02115

Received 27 May 1998/Accepted 16 July 1998

Previously, we found that the cause of autosomal dominant selective tooth agenesis in one family is a missense mutation resulting in an arginine-to-proline substitution in the homeodomain of MSX1. To determine whether the tooth agenesis phenotype may result from haploinsufficiency or a dominant-negative mechanism, we have performed biochemical and functional analyses of the mutant protein Msx1(R31P). We show that Msx1(R31P) has perturbed structure and reduced thermostability compared with wild-type Msx1. As a consequence, the biochemical activities of Msx1(R31P) are severely impaired, since it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. We also show that Msx1(R31P) is inactive in vivo, since it does not display the activities of wild-type Msx1 in assays of ectopic expression in the limb. Furthermore, Msx1(R31P) does not antagonize the activity of wild-type Msx1 in any of these assays. Because Msx1(R31P) appears to be inactive and does not affect the action of wild-type Msx1, we propose that the phenotype of affected individuals with selective tooth agenesis is due to haploinsufficiency.

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^* Corresponding author. Mailing address: CABM, 679 Hoes Lane, Piscataway, NJ 08854. Phone: (732) 235-5161. Fax: (732) 235-4850. E-mail: abate{at}mbcl.rutgers.edu.

Present address: Division of Growth and Developmental Sciences and Division of Basic Sciences, New York University College of Dentistry, New York, NY 10010.

Present address: Department of Molecular and Cellular Biology, Division of Genetics, University of California, Berkeley, CA 94720.

^§ Present address: Center for Cancer Research, Department of Biology, MIT, Cambridge, MA 02139.

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Molecular and Cellular Biology, October 1998, p. 6044-6051, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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