Human Molecular Genetics, 2001, Vol. 10, No. 16 1673-1677
© 2001 Oxford University Press
Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta
School of Biological Sciences and Department of Dental Medicine and Surgery, 3.239 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK, 1Department of Paediatric Dentistry, Edinburgh Dental Institute, Lauriston Building, Lauriston Place, Edinburgh EH13 9YW, UK, 2Centre for Nephrology, University College London, Middlesex Hospital, Mortimer Street, London W1N 8AA, UK and 3Dental Health Unit, Manchester Science Park, Lloyd Street North, Manchester M15 4SH, UK
Received April 5, 2001; Revised and Accepted June 5, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Amelogenesis imperfecta (AI) is a group of inherited defects of dental enamel formation that shows both clinical and genetic heterogeneity. To date, mutations in the gene encoding amelogenin have been shown to underlie a subset of the X-linked recessive forms of AI. Although none of the genes underlying autosomal-dominant or autosomal-recessive AI have been identified, a locus for a local hypoplastic form has been mapped to human chromosome 4q11–q21. In the current investigation, we have analysed a family with an autosomal-dominant, smooth hypoplastic form of AI. Our results have shown that a splicing mutation in the splice donor site of intron 7 of the gene encoding the enamel-specific protein enamelin underlies the phenotype observed in this family. This is the first autosomal-dominant form of AI for which the genetic mutation has been identified. As this type of AI is clinically distinct from that localized previously to chromosome 4q11–q21, these findings highlight the need for a molecular classification of this group of disorders.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Dental enamel is a highly mineralized tissue with
85% of its volume occupied by unusually large, highly organized, hydroxyapatite crystals. Enamel is unique among the mineralized tissues in that it is produced by ameloblasts, which have an epithelial origin. Amelogenesis imperfecta (AI) is a common group of inherited defects of dental enamel formation that exhibit marked genetic and clinical heterogeneity with at least 14 different sub-types being recognized on the basis of their clinical appearance (1). Taking all forms of AI into account, the prevalence has been reported to be as high as 1:700 in northern Sweden (2). Affected individuals show either hypoplastic (thin but seemingly correctly mineralized) or hypomineralized enamel, but an overlap of these signs is seen in many cases (3). There is no apparent correlation between the phenotype and the mode of inheritance with autosomal-dominant, autosomal-recessive and X-linked recessive forms being recognized. To date, mutations in the gene encoding the protein amelogenin have been shown to cause some X-linked recessive forms of AI. This locus has been designated AIH1 (4–11). The heterogeneity that characterizes this group of disorders has limited further progress to the identification of additional loci by linkage analysis; however, the underlying genes have not been identified. For example, a second locus for X-linked recessive AI, AIH3, has been mapped to chromosome Xq24–q27.1 (12). Similarly, an autosomal-dominant, local hypoplastic form of AI (AIH2) has been mapped to a 4 Mb region of human chromosome 4q11–q21 that encompasses the gene encoding the ameloblast-specific protein ameloblastin, AMBN (13–15). Recently, the gene encoding a second ameloblast-specific protein, enamelin, has been mapped to the AIH2 critical region within 15 kb of AMBN (16,17). Nevertheless, the genetic mutation underlying this form of AI has not been identified and additional genetic linkage studies have indicated that other genetic loci for autosomal forms of AI exist (18). In the current study, we have shown that a clinically distinct form of AI, thin and smooth hypoplastic AI, which has been estimated to account for 1.5% of cases of AI (3), maps to the AIH2 critical region and that this type of AI results from mutation of the gene encoding enamelin. |
RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We are taking a positional candidate approach to identify the genetic mutations underlying the various forms of AI and have investigated a family with an autosomal-dominant form of this condition (Fig. 1A). All affected members of the family exhibit enamel hypoplasia in both the deciduous and permanent dentitions. Clinically, the teeth appear small, thin and yellow due to a lack of enamel thickness (Fig. 1B and C). Such dentitions have been classified according to the clinical appearance as thin and smooth hypoplastic AI (1). As nephrocalcinosis may be associated with this dental phenotype (19,20), all affected individuals were screened with renal ultrasonography, but none was evident.
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Although this form of AI is clinically distinct from that previously localized to chromosome 4q, we commenced our analysis in this region of the genome. Initially, we focussed our attention on the AMBN locus and identified a short tandem repeat polymorphism in intron 11 of this gene. Segregation analysis revealed no evidence for recombination between AMBN and the disease phenotype in this family (Zmax = 2.06) suggesting linkage to chromosome 4q11–q21. Mutation screening of all 13 exons of AMBN (21) by single-strand conformation polymorphism (SSCP) analysis failed to reveal any AI-specific mobility shifts in this gene. As these results effectively excluded mutations in AMBN from a causative role in the pathogenesis of the AI in this family, we extended our studies to the gene encoding enamelin, which has recently been shown to map within 15 kb of AMBN (16). RT–PCR analysis showed that in the panel of human cDNAs tested, enamelin transcript could only be detected in cDNA derived from tooth germs (Fig. 2A) extending previous results from the rabbit, pig and mouse to man (17,22,23).
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In silico screening of the genomic sequence of human chromosome 4 with human cDNA sequence using the BLAST algorithm subsequently indicated that the gene encoding enamelin contains nine exons, separated by eight introns. All of the intron–exon boundaries were found to be type 0, with splicing occurring between exons and the splice donor and acceptor sites conforming to the published consensus sequences (24) (Table 1). SSCP analysis performed using primers designed to screen each exon and the associated splice junctions for mutations, revealed an abnormal conformer that was present in all affected family members, but not the unaffected individuals (Fig. 2B). Direct sequencing revealed a heterozygous mutation in the splice donor site of intron 7, nt841+1 (G
A) (Fig. 2C). This mutation deletes an HphI site, which allowed us to confirm that the mutation co-segregates with the disease phenotype (Fig. 2D). The mutation was not detected in 200 control chromosomes of similar ethnic origin.
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DISCUSSION |
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Recent evidence from genetic studies has implicated a number of molecules in the biomineralization events underlying tooth development. For example, mutation of the dentine sialophosphoprotein gene causes dentinogenesis imperfecta type II (25,26). However, this condition is thought to be genetically homogeneous. Conversely, the search for the genetic mutations underlying AI has been frustrated by the clinical and genetic heterogeneity observed in this condition. Progress in this area has been limited to the finding that mutations in the gene encoding amelogenin underlie a subset of cases of X-linked recessive AI (4–11) and the delineation of at least three additional genetic loci (12,13,18). Here we report the first genetic mutation underlying an autosomal form of AI, thereby providing definitive evidence that enamelin is essential for dental enamel formation. Moreover, we demonstrate that the locus for smooth hypoplastic AI maps to the same genetic interval as that for the clinically distinct local hypoplastic form. Therefore, our findings suggest that these two AI subtypes are allelic and support the need for a molecular classification of this heterogeneous group of disorders (27).
The calcium phosphate hydroxyapatite crystals that comprise the bulk of the mature enamel are unusually large, uniform and regularly disposed within the tissue. This highly organized and unusual structure is thought to be rigorously controlled through the interaction of a number of organic matrix molecules that include amelogenin, enamelin, ameloblastin, tuftelin, dentine sialophosphoprotein and a variety of enzymes (28). In porcine enamel, enamelin is synthesized and secreted by ameloblasts as a 186 kDa precursor, the unprocessed form concentrating along the secretory face of the ameloblast Tomes process. Proteolytic processing towards the C-terminus produces 142 kDa enamelin via a 155 kDa intermediate. Subsequent cleavages generate an 89 kDa polypeptide encompassing the first 627 amino acids of the secreted protein and a 34 kDa polypeptide beginning at residue 632. Processing of 89 kDa enamelin results in polypeptides of 32 kDa (amino acids 136–238) and 25 kDa, commencing at residue 477 (29). Intact enamelin and cleavage products containing the C-terminus are limited to the most superficial layer of the developing enamel matrix, while other cleavage products accumulate in the deeper layers of this tissue in the maturing rod and inter-rod enamel (30).
Due to the ameloblast-specific nature of enamelin and the transient nature of ameloblasts during development, it was not possible to prepare cDNA from affected individuals to confirm the effect of the mutation on the enamelin transcript. Nevertheless, numerous studies have demonstrated that mutations of the type observed in this study lead to aberrant splicing (31). While skipping of exon 7 remains the most likely scenario, a failure of splicing at the splice donor site of intron 7 with read through into the intron remains a possibility. In the latter case, this would result in the introduction of a termination codon after nine amino acids with the likely loss of enamelin protein function due to nonsense-mediated mRNA degradation (32). Conversely, exon skipping would result in an in-frame deletion of the 21 amino acids encoded by exon 7. Alignment of the amino acid sequences of porcine and human enamelin indicates that deletion of exon 7 would remove the 32 kDa proteolytic cleavage site. Among the enamelin cleavage products, the 32 kDa polypeptide is the most characterized. For example, it undergoes phosphorylation and asparagine-linked glycosylation (29,33). Moreover, 32 kDa enamelin has been proposed to play a role in amelogenin processing (34). Intriguingly, amelogenin processing products have been suggested to inhibit hydroxyapatite crystal growth during amelogenesis, and removal of such inhibitory proteins is thought to be crucial to enamel maturation (28). Although the 89 kDa precursor polypeptide is also active, cleavage to the 32 kDa form in immature enamel to from ‘amelogeninase’ has been proposed to be essential for full function in degrading amelogenins in maturing enamel (34). The 32 kDa enamelin polypeptide may therefore play an important role in enamel mineralization in vivo, and a failure of enamelin cleavage with resulting reduced ‘amelogeninase’ activity may account for the mechanism underlying the amelogenesis imperfecta observed in this family. The delineation of additional mutations in families with a history of AI and complementary functional studies will be important in clarifying this hypothesis.
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MATERIALS AND METHODS |
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Family
The pedigree of the family is presented in Figure 1A. Each member of the family was examined clinically and, where appropriate, radiographically by K.Harley. Renal sonography of affected individuals was performed by C.Laing.
RT–PCR
Total RNA was either extracted according to the method of Chomczynski and Saachi (35) or purchased commercially. RT–PCR analyses were performed and analysed as described previously (36) using a forward primer in exon 6 (5'-CATAACAAGACTGATCAGACC-3') and a reverse primer in exon 9 (5'-ACTGGATTTCCTGGACGAGC-3') of the enamelin gene. These primers generate an amplicon of 797 bp from cDNA.
Mutation analysis
SSCP analysis of genomic DNA extracted from peripheral blood leucocytes was performed according to the method of Orita et al. (37) using the primers 5'-TTTTCAATACCACATCACTCTG-3' and 5'-ACTGATTGGTATATGGTATTCC-3'. To determine the sequence variant underlying the SSCP mobility shift, PCR products were sequenced directly via the dideoxy chain termination method using dye primer chemistry. To confirm that the mutation co-segregated with the disease phenotype, PCR amplified genomic DNA was digested with the restriction enzyme HphI and the resulting products were resolved on a 9% polyacrylamide gel.
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ACKNOWLEDGEMENTS |
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We thank the test family for providing samples. This work is supported by an MRC Industrial Collaborative Studentship with Colgate (G216/4098) and by the Wellcome Trust (051938).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 161 275 5620; Fax: +44 161 275 5620; Email: mike.dixon@man.ac.uk
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REFERENCES |
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