Abstract
We demonstrate that a mutation in the homeobox gene, MSX1, causes a common developmental anomaly, familial tooth agenesis. Genetic linkage analyses in a family with autosomal dominant agenesis of second premolars and third molars identified a locus on chromosome 4p, where the MSX1 gene resides. Sequence analyses demonstrated an Arg31 Pro missense mutation in the homeodomain of MSX1 in all affected family members. Arg 31 is a highly conserved homeodomain residue that interacts with the ribose phosphate backbone of target DMA. We propose that the Arg31 Pro mutation compromises MSX1 interactions, and suggest that MSX1 functions are critical for normal development of specific human teeth.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
McKusick, V.A. Mendelian Inheritance in Man 11th edn.(The Johns Hopkins University Press, Baltimore, 1994).
Graber, L.W. Congenital absence of teeth: a review with emphasis on inheritance patterns. J. Am. Dent Assoc. 96, 266–275 (1978).
Gorlin, R., Cohen, M. & Levin, L. Syndromes of the Head and Neck. (Oxford University Press, New York, 1990).
Burzynski, N.J. & Escobar, V.H. Classification and genetics of numeric anomalies of dentition. Birth Defects. 19, 95–106 (1983).
Symons, A.L., Stritzel, F. & Stamatiou, J. Anomalies associated with hypodontia of the permanent lateral incisor and second premolar. J. Clin. Pediat. Dent. 17, 109–111 (1993).
Sharpe, P.T. Homeobox genes and orofacial development. Connect. Tissue. Res. 32, 17–25 (1995).
Jowett, A.K., Vainio, S., Ferguson, M.W., Sharpe, P.T. & Thesleff, I. Epithelial-mesenchymal interactions are required for msxl and msx2 gene expression in the developing murine molar tooth. Development 117, 461–470 (1993).
Robert, B., Sassoon, D., Jacq, B., Gehring, W. & Buckingham, M., Hox-7, a mouse homeobox gene with a novel pattern of expression during embryogenesis. EMBO J. 8, 91–100 (1989).
Satokata, I. & Maas, R. Msxl deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–356 (1994).
Gyapay, G. et al. The 1993–p94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).
Murray, J.C., et al. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science 265, 2049–2054 (1994).
Padanilam, B.J. . et al. Characterization of the human HOX 7 cDNA and identification of polymorphic markers. Hum. Mol. Genet. 1, 407–410 (1992).
Genome Data Base. Chromosome 4.
Ferguson, M. Craniofacial malformations: towards a molecular understanding. Nature Genet. 6, 329–330 (1994).
Hewitt, J.E., Clark, L.N., Ivens, A. & Williamson, R. Structure and sequence of the human homeobox gene HOX7. Genomics 11, 670–678 (1991).
Davidson, D. The function and evolution of Msx genes: pointers and paradoxes. Trends Genet. 11, 405–411 (1995).
Nieminen, P., Arte, S., Pirinen, S., Peltonen, L. & Thesleff, I. Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes. Hum. Genet. 96, 305–308 (1995).
Gehring, W.J. et al. Homeodomain-DNA recognition. Cell 78, 211–223 (1994)
Muller, M. et al. Isolation and sequence-specific DNA binding of the Antennapedia homeodomain. EMBO J. 7, 4299–4304 (1988).
Laughon, A. DNA binding specificity of homeodomains. Biochemistry 30, 11357–11367 (1991).
Zhang, H., Catron, K. & Abate-Shen, C. A role for the Msx-1 homeodomain in transcriptional regulation: Residues in the N-terminal arm mediate TATA binding protein interactions and transcriptional repression. Proc. Natl. Acad. Sci. USA 93, 1764–1769 (1996).
Watkins, H. et al. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1 q3. Nature Genet. 3, 333–337 (1993).
Ausubel, F. et al. Current Protocols in Molecular Biology. (Greene Publishing, New York, 1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vastardis, H., Karimbux, N., Guthua, S. et al. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet 13, 417–421 (1996). https://doi.org/10.1038/ng0896-417
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0896-417
This article is cited by
-
Compound heterozygous WNT10A missense variations exacerbated the tooth agenesis caused by hypohidrotic ectodermal dysplasia
BMC Oral Health (2024)
-
“Examining the link between tooth agenesis and papillary thyroid cancer: is there a risk factor?” Observational study
Progress in Orthodontics (2024)
-
Novel frameshift variant of WNT10A in a Japanese patient with hypodontia
Human Genome Variation (2024)
-
Occlusal characteristics in modern humans with tooth agenesis
Scientific Reports (2024)
-
The genetic basis of hypodontia in dental development
British Dental Journal (2023)