Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature
Introduction
The amelogenesis imperfectas (AI) are a clinically and genetically heterogeneous group of disorders that adversely affect enamel development causing abnormalities in the amount, structure, and composition of enamel. While altered enamel is the major feature of AI, other craniofacial anomalies including an obtuse gonial angle and cranial base changes have been reported.1., 2. Altered craniofacial structures can manifest as a skeletal open bite and be present in 25–40% of affected individuals.1., 3., 4. Non-tooth related craniofacial skeletal findings that are associated with some cases of AI may represent environmental influences, pleiotropic effects of the underlying gene mutation or modifying gene effects.1., 3., 4.
AI can be inherited as an X-linked, autosomal dominant or autosomal recessive trait. Specific gene mutations have been identified for only two AI loci: the AMELX gene (OMIM 606585) on chromosome Xp21 and the enamelin (ENAM) gene (OMIM300391) on chromosome 4q21.5., 6., 7., 8. Twelve different mutations in the AMELX gene have been identified and, depending on the mutation, the phenotype can vary from thin hypoplastic enamel to enamel that is normal in thickness but has a reduced mineral content and increased protein content.9 Amelogenin (product of the AMELX gene) is the most abundant extracellular matrix protein in developing enamel and is thought to be critical for normal enamel crystallite morphology and growth, and ultimately, the exquisitely intricate enamel prism architecture.10 In addition to amelogenin, there are numerous other extracellular matrix components in developing enamel, including proteins such as ameloblastin, enamelin and proteinases that are required to process the matrix proteins during mineralization.11., 12., 13. Enamelin (product of the ENAM gene) is considered to be an enamel specific protein secreted by ameloblasts and is localized at the secretory face of this cell.14 Enamelin is a glycosylated protein secreted in relatively low amounts (1–5% of matrix).15., 16. The first gene mutation associated with an autosomal AI type was recently identified as a single base substitution in the GT splice donor site of intron 8 of the enamelin gene.8
Two clinically distinct forms of autosomal dominant AI, smooth hypoplastic AI and local hypoplastic AI, are associated with ENAM mutations.6., 8. Smooth hypoplastic AI has generalized severe reduction in enamel thickness while the local hypoplastic AI type is characterized by enamel that is generally of normal thickness but has horizontal bands of enamel pits that circumnavigate the tooth. The clinically distinct phenotypes resulting from these allelic mutations are believed to result from haploinsufficiency in local hypoplastic AI and from a dominant negative effect in the more severe generalized smooth hypoplastic AI.6 A third reported ENAM mutation is associated with a variable phenotype ranging from generalized thin hypoplastic enamel to local hypoplastic enamel that primarily affects the middle third of the crown.17
In this report we document an unrelated kindred with the same mutation as that described by Kida et al.17 This ENAM mutation is associated with a variable phenotype that ranges from smooth hypoplastic AI to a pitted and rough surface overlying a generalized thin enamel covering. We also present the first detailed characterization of the enamel phenotype resulting from this mutation, including the enamel ultrastructure. The emerging importance of phenotype-genotype correlations for the AI diseases and the need to describe future ENAM mutations in a standard format leads us to present a comprehensive nomenclature for AI associated with mutations of the ENAM gene. Such a system was recently adopted for AMELX forms of X-linked AI.5
Section snippets
Family and phenotype analyses
This study was approved by the University of North Carolina and the University of Pittsburgh Institutional Review Board and all participants provided written consent prior to enrollment. The family shown in Fig. 1A was ascertained from an affected proband (III-9) that had generalized thin hypoplastic enamel (Fig. 1B). All available family members (N=14) were examined clinically and radiographically to determine affection status and to characterize the clinical phenotype. Two unerupted third
Results
The kindred was determined to be of Lebanese origin and 14 family members were evaluated for the study. Eight affected and six unaffected family members were studied (Fig. 1A). Pedigree analysis showed the AI trait was present in all generations with approximately equal numbers of affected males and females. In addition, male-to-male transmission of the AI trait was noted in this family, all characteristics consistent with autosomal dominant transmission. Clinical evaluation showed that none of
Discussion
While it has long been recognized that there are multiple clinical forms of AI, it is only recently that the genetic bases of these heterogeneous conditions are being identified. As the underlying genetic etiologies for AI are elucidated, we have begun to establish genotype–phenotype correlations for these clinically and genetically diverse disorders. This carries significant implications for understanding the molecular mechanisms leading to the unique AI enamel phenotypes and ultimately for
Acknowledgements
This work was supported by the National Institutes of Health NIDCR grant DE12879.
References (27)
- et al.
An investigation of the association between anterior open-bite and amelogenesis imperfecta
Am. J. Orthodont.
(1982) - et al.
Establishment of a nomenclature for X-linked amelogenesis imperfecta
Arch. Oral Biol.
(2002) - et al.
Calcium binding of enamel proteins and their derivatives with emphasis on the calcium-binding domain of porcine sheathlin
Arch. Oral Biol.
(2001) - et al.
Craniofacial features associated with amelogenesis imperfecta
J. Craniofac. Genet. Dev. Biol.
(1999) Analysis of a kindred with amelogenesis imperfecta
J. Oral. Pathol.
(1985)- et al.
Facial morphology and open bite deformity in amelogenesis imperfecta
Acta Odontol. Scand.
(1982) - et al.
A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta AIH
Hum. Mol. Genet.
(2002) - Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: Center for Medical Genetics, Johns Hopkins University and...
- et al.
Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta
Hum. Mol. Genet.
(2001) - et al.
Relationship of phenotype and genotype in X-linked amelogenesis imperfecta
Connect. Tissue Res.
(2003)
Molecular mechanisms of dental enamel formation
Crit. Rev. Oral. Biol. Med.
Cloning human enamlelin cDNA, chromosomal localization and analysis of expression during tooth development
J. Dent. Res.
Full-length sequence, localization, and chromosomal mapping of ameloblastin
J. Biol. Chem.
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