Candidate genes for amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are located on 4q21 in humans. We tested our hypothesis that mutations in the portion of mouse chromosome 5 corresponding to human chromosome 4q21 would cause enamel and dentin abnormalities. Male C3H mice were injected with ethylnitrosourea (ENU). Within a dominant ENU mutagenesis screen, a mouse mutant was isolated with an abnormal tooth enamel (ATE) phenotype. The structure and ultrastructure of teeth were studied. The mutation was located on mouse chromosome 5 in an interval of 9 cM between markers D5Mit18 and D5Mit10. Homozygotic mutants showed total enamel aplasia with exposed dentinal tubules, while heterozygotic mutants showed a significant reduction in enamel width. Dentin of mutant mice showed a reduced content of mature collagen cross-links. We were able to demonstrate that a mutation on chromosome 5 corresponding to human chromosome 4q21 can cause amelogenesis imperfecta and changes in dentin composition.
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References
1.
Açil Y, Müller PK (1994). A rapid method for the isolation of the mature collagen cross-links, hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP). J Chromatogr A664:183–188.
2.
Açil Y, Springer ING, Prasse JG, Hedderich J, Jepsen S (2002). Concentration of collagen cross-links in human dentin bears no relation to the individual age. Int J Legal Med116:340–343.
3.
Aldred MJ, Crawford PJ (1995). Amelogenesis imperfecta—towards a new classification. Oral Dis1:2–5.
4.
Aldred MJ, Crawford PJ (1997). Molecular biology of hereditary enamel defects. Ciba Found Symp205:200–209.
5.
Aldred MJ, Savarirayan R, Crawford PJ (2003). Amelogenesis imperfecta: a classification and catalogue for the 21st century. Oral Dis9:19–23.
6.
Dai XF, Ten Cate AR, Limeback H (1991). The extent and distribution of intratubular collagen fibrils in human dentine. Arch Oral Biol36:775–778.
7.
Donath K, Breuner G (1982). A method for the study of undecalcified bones and teeth with attached soft tissues. The Säge-Schliff (sawing and grinding) technique. J Oral Pathol11:318.
8.
Eyre D (1992). New biomarkers of bone resorption. J Clin Endocrinol Metab74:470A–470C.
9.
Gibson C, Golub E, Herold R, Risser M, Ding W, Shimokawa H, et al. (1991). Structure and expression of the bovine amelogenin gene. Biochemistry30:1075–1079.
10.
Gibson CW, Yuan ZA, Hall B, Longenecker G, Chen E, Thyagarajan T, et al. (2001). Amelogenin-deficient mice display an amelogenesis imperfecta phenotype. J Biol Chem276:31871–3185.
11.
Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, et al. (2003). Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects. J Med Genet40:900–906.
12.
Hrabe de Angelis M, Balling R (1998). Large scale ENU screens in the mouse: genetics meets genomics. Mutat Res400:25–32.
13.
Hrabe de Angelis MH, Flaswinkel H, Fuchs H, Rathkolb B, Soewarto D, Marschall S, et al. (2000). Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat Genet25:444–447.
14.
Hu JC, Zhang CH, Yang Y, Karrman-Mardh C, Forsman-Semb K, Simmer JP (2001). Cloning and characterization of the mouse and human enamelin genes. J Dent Res80:898–902.
15.
Kida M, Ariga T, Shirakawa T, Oguchi H, Sakiyama Y (2002). Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an enamelin gene mutation at the exon-intron boundary. J Dent Res81:738–742.
16.
Lee SK, Kim SM, Lee YJ, Yamada KM, Yamada Y, Chi JG (2003). The structure of the rat ameloblastin gene and its expression in amelogenesis. Mol Cells15:216–225.
17.
MacDougall M, DuPont BR, Simmons D, Reus B, Krebsbach P, Karrman C, et al. (1997). Ameloblastin gene (AMBN) maps within the critical region for autosomal dominant amelogenesis imperfecta at chromosome 4q21. Genomics41:115–118.
18.
MacDougall M, Jeffords LG, Gu TT, Knight CB, Frei G, Reus BE, et al. (1999). Genetic linkage of the dentinogenesis imperfecta type III locus to chromosome 4q. J Dent Res78:1277–1282.
19.
Malmgren B, Lindskog S, Elgadi A, Norgren S (2004). Clinical, histopathologic, and genetic investigation in two large families with dentinogenesis imperfecta type II. Hum Genet114:491–498.
20.
Mardh CK, Backman B, Holmgren G, Hu JC, Simmer JP, Forsman-Semb K (2002). A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2). Hum Mol Genet11:1069–1074.
21.
Nagano T, Oida S, Ando H, Gomi K, Arai T, Fukae M (2003). Relative levels of mRNA encoding enamel proteins in enamel organ epithelia and odontoblasts. J Dent Res82:982–986.
22.
Perdigão J, Frankenberger R, Rosa BT, Breschi L (2000). New trends in dentin/enamel adhesion. Am J Dent13(Spec Iss):25D–30D.
23.
Rajpar MH, Harley K, Laing C, Davies RM, Dixon MJ (2001). Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta. Hum Mol Genet10:1673–1677.
24.
Sachs L (1992). Angewandte Statistik. Berlin: Springer Verlag, pp. 510–515.
25.
Shore RC, Backman B, Brookes SJ, Kirkham J, Wood SR, Robinson C (2002). Inheritance pattern and elemental composition of enamel affected by hypomaturation amelogenesis imperfecta. Connect Tissue Res43:466–471.
26.
Springer ING, Suhr M, Fleiner B (2002). Adaptive adjustment of the adolescent porcine mandibular condyle. Bone31:1190–1195.
27.
Springer ING, Terheyden H, Dunsche A, Czech N, Tiemann M, Hedderich J, Açil Y (2003). Collagen crosslink excretion and staging of oral cancer. Br J Cancer88:1105–1110.
28.
Sundell S, Valentin J (1986). Hereditary aspects and classification of hereditary amelogenesis imperfecta. Community Dent Oral Epidemiol14:211–216.
29.
Winter GB, Brook AH (1975). Enamel hypoplasia and anomalies of the enamel. Dent Clin North Am19:3–24.
30.
Wright JT, Robinson C, Shore R (1991). Characterization of the enamel ultrastructure and mineral content in hypoplastic amelogenesis imperfecta. Oral Surg Oral Med Oral Pathol72:594–601.
31.
Xiao S, Yu C, Chou X, Yuan W, Wang Y, Bu L, et al. (2001). Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nat Genet27:201–204.
