Previous Article | Next Article 
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-Shen1,2,*
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.
*
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.
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.
This article has been cited by other articles:
-
Matalova, E., Fleischmannova, J., Sharpe, P.T., Tucker, A.S.
(2008). Tooth Agenesis: from Molecular Genetics to Molecular Dentistry. JDR
87: 617-623
[Abstract]
[Full Text]
-
Takahashi, H., Kamiya, A., Ishiguro, A., Suzuki, A. C., Saitou, N., Toyoda, A., Aruga, J.
(2008). Conservation and Diversification of Msx Protein in Metazoan Evolution. Mol Biol Evol
25: 69-82
[Abstract]
[Full Text]
-
Modesto, A., Moreno, L.M., Krahn, K., King, S., Lidral, A.C.
(2006). MSX1 and Orofacial Clefting with and without Tooth Agenesis. JDR
85: 542-546
[Abstract]
[Full Text]
-
Liu, W., Sun, X., Braut, A., Mishina, Y., Behringer, R. R., Mina, M., Martin, J. F.
(2005). Distinct functions for Bmp signaling in lip and palate fusion in mice. Development
132: 1453-1461
[Abstract]
[Full Text]
-
Mensah, J. K., Ogawa, T., Kapadia, H., Cavender, A. C., D'Souza, R. N.
(2004). Functional Analysis of a Mutation in PAX9 Associated with Familial Tooth Agenesis in Humans. J. Biol. Chem.
279: 5924-5933
[Abstract]
[Full Text]
-
Nieminen, P., Kotilainen, J., Aalto, Y., Knuutila, S., Pirinen, S., Thesleff, I.
(2003). MSX1 Gene is Deleted in Wolf-Hirschhorn Syndrome Patients with Oligodontia. JDR
82: 1013-1017
[Abstract]
[Full Text]
-
Frazier-Bowers, S A, Pham, K Y, Le, E V, Cavender, A C, Kapadia, H, King, T M, Milewicz, D M, D'Souza, R N
(2003). A unique form of hypodontia seen in Vietnamese patients: cinical and molecular analysis. J. Med. Genet.
40: e79-79
[Full Text]
-
Chai, Y., Ito, Y., Han, J.
(2003). TGF-{beta} SIGNALING AND ITS FUNCTIONAL SIGNIFICANCE IN REGULATING THE FATE OF CRANIAL NEURAL CREST CELLS. CROBM
14: 78-88
[Abstract]
[Full Text]
-
Kobayashi, H., Kruger, R., Markopoulou, K., Wszolek, Z., Chase, B., Taka, H., Mineki, R., Murayama, K., Riess, O., Mizuno, Y., Hattori, N.
(2003). Haploinsufficiency at the {alpha}-synuclein gene underlies phenotypic severity in familial Parkinson's disease. Brain
126: 32-42
[Abstract]
[Full Text]
-
Debeer, P, Bacchelli, C, Scambler, P J, De Smet, L, Fryns, J-P, Goodman, F R
(2002). Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13. J. Med. Genet.
39: 852-856
[Full Text]
-
Pizette, S., Abate-Shen, C., Niswander, L.
(2001). BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development
128: 4463-4474
[Abstract]
[Full Text]
-
Hu, G., Lee, H., Price, S. M., Shen, M. M., Abate-Shen, C.
(2001). Msx homeobox genes inhibit differentiation through upregulation of cyclin D1. Development
128: 2373-2384
[Abstract]
[Full Text]
-
Blin-Wakkach, C., Lezot, F., Ghoul-Mazgar, S., Hotton, D., Monteiro, S., Teillaud, C., Pibouin, L., Orestes-Cardoso, S., Papagerakis, P., Macdougall, M., Robert, B., Berdal, A.
(2001). Endogenous Msx1 antisense transcript: In vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals. Proc. Natl. Acad. Sci. USA
10.1073/pnas.131497098v1
[Abstract]
[Full Text]
-
Pellizzari, L., D'Elia, A., Rustighi, A., Manfioletti, G., Tell, G., Damante, G.
(2000). Expression and function of the homeodomain-containing protein Hex in thyroid cells. Nucleic Acids Res
28: 2503-2511
[Abstract]
[Full Text]
-
Bendall, A., Ding, J, Hu, G, Shen, M., Abate-Shen, C
(1999). Msx1 antagonizes the myogenic activity of Pax3 in migrating limb muscle precursors. Development
126: 4965-4976
[Abstract]
-
Blin-Wakkach, C., Lezot, F., Ghoul-Mazgar, S., Hotton, D., Monteiro, S., Teillaud, C., Pibouin, L., Orestes-Cardoso, S., Papagerakis, P., Macdougall, M., Robert, B., Berdal, A.
(2001). Endogenous Msx1 antisense transcript: In vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals. Proc. Natl. Acad. Sci. USA
98: 7336-7341
[Abstract]
[Full Text]