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Amelogenin p.M1T and p.W4S Mutations Underlying Hypoplastic X-linked Amelogenesis Imperfecta

¹ Department of Orthodontics and Pediatric Dentistry, University of Michigan Dental Research Lab, 1210 Eisenhower Place, Ann Arbor, MI 48108;
² Seoul National University, College of Dentistry, Department of Pediatric Dentistry & Dental Research Institute, 28-2 Yongon-dong, Chongno-gu, Seoul, Korea 110-768;
³ University of Texas Health Science Center at San Antonio, Department of Pediatric Dentistry, 7703 Floyd Curl Drive, San Antonio, TX 78289-3900;
⁴ The University of North Carolina at Chapel Hill, School of Dentistry, Dental Research Center, Chapel Hill, NC 27599-7455; and
⁵ Department of Preventive Sciences, Moos Health Sciences Tower, 515 Delaware Street SE, Minneapolis, MN 55455;

^* corresponding author, janhu{at}umich.edu

	ABSTRACT

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Mutations in the human amelogenin gene (AMELX, Xp22.3) cause a phenotypically diverse set of inherited enamel malformations. We hypothesize that the effects of specific mutations on amelogenin protein structure and expression will correlate with the enamel phenotype, clarify amelogenin structure/function relationships, and improve the clinical diagnosis of X-linked amelogenesis imperfecta (AI). We have identified two kindreds with X-linked AI and characterized the AMELX mutations underlying their AI phenotypes. The two missense mutations are both in exon 2 and affect the translation initiation codon and/or the secretion of amelogenin (p.M1T and p.W4S), resulting in hypoplastic enamel. Primary anterior teeth from affected females with the p.M1T mutation were characterized by light and scanning electron microscopy. The thin enamel had defective prism organization, and the surface was rough and pitted. Dentin was normal. The severity of the enamel phenotype correlated with the predicted effects of the mutations on amelogenin expression and secretion.

KEY WORDS: enamel • amelogenin • amelogenesis imperfecta • hypoplastic AI • AMELX

	INTRODUCTION

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In humans, amelogenin genes are located on the X and Y chromosomes (Lau et al., 1989; Nakahori et al., 1991). In males (XY), 90% of the amelogenin transcripts are expressed from AMELX, and only 10% are expressed from AMELY (Salido et al., 1992). Mutational analyses have identified 12 different AMELX mutations in kindreds afflicted with X-linked AI (Hart et al., 2002). The AMELX mutations include missense and nonsense mutations and deletions of various sizes, which result in markedly different enamel phenotypes. A recent study of phenotype/genotype correlations in kindreds expressing defined AMELX mutations noted a clustering of AI phenotypes according to their effects on the translated amelogenin protein (Wright et al., 2003).

Two mutations have been identified in the coding region for the amelogenin signal peptide (MGTWILFACLLGAAFA). The first mutation involved the deletion of 9 nucleotides that replaced amino acids 5 through 8 (ILFA) with threonine (T) (Lagerström-Fermer et al., 1995). This I5-A8delinsT mutation caused the synthesis of a normal amelogenin protein fused to a defective signal peptide. Clinically, the incisal edges of the anterior teeth showed prominent mammelons, and the enamel was thinner than normal but appeared to be properly mineralized. The female carriers were less severely affected, with islands of alternating normal and defective enamel. The second signal peptide defect was a point mutation (W4X) that also caused severe enamel hypoplasia (Sekiguchi et al., 2001). The thin enamel had a slightly coarse surface, and the incisal edges of the anterior teeth were rough due to exaggerated mammelons and incisal chipping. The presence or absence of a vertical banding pattern in the dentition of the affected female was not reported. The translational stop signal replacing the fourth codon (W4X) might have resulted in a null mutation, but because an upstream short reading frame often allows ribosomes to re-initiate at appropriate downstream start codons (Kozak, 1984), such a mutation might also have caused translation to initiate from the Met17 codon, resulting in the intracellular expression of the normally secreted amelogenin protein.

Here we report two AMELX mutations (p.M1T and p.W4S) within the coding region for the amelogenin signal peptide, which brings to four the number of mutations predicted to interfere with the secretion of amelogenin. The common phenotype in these four kindreds is enamel hypoplasia with malformed incisal edges on the anterior teeth. The enamel appears to have mineralized normally and contrasts with dentin on radiographs. In the case of the four signal peptide mutations in AMELX, there is a strong correlation between phenotype and genotype, which could help clinicians in making a diagnosis of X-linked AI.

	MATERIALS & METHODS

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Identification of Kindreds and Enrollment of Human Subjects
Two eight-year-old female patients from unrelated families were identified as having AI. Pedigrees were constructed based upon oral histories. In both families, affected individuals were identified in all generations, and the number of affected females greatly exceeded the number of affected males. These observations suggested that the mode of inheritance was likely to be X-linked, and that the underlying mutation would be in the amelogenin gene. Members of both kindreds were recruited for AMELX mutational analysis. The study protocol and patient consents were reviewed and approved by the Institution Review Boards at the University of Texas Health Science Center at San Antonio and at the University of Michigan.

Polymerase Chain-reaction (PCR) and DNA Sequencing
A 10-cc quantity of peripheral whole blood was obtained from participating family members. Genomic DNA was isolated with the use of the QIAamp DNA Blood Maxi Kit (Qiagen Inc., Valencia, CA, USA). The purity and concentration of the DNA were quantitated by spectrophotometry, as measured by the OD₂₆₀/OD₂₈₀ ratio.

Oligonucleotide primers for polymerase chain-reaction were designed with the use of Primer3 on the Web (http://www-genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi) (Rozen and Skaletsky, 2000). The strategy was to generate amplification products that would allow for DNA sequencing, in both directions, of each amelogenin exon and ~ 50 bp of their adjoining introns. The oligonucleotide sequences, their annealing sites, and the sizes of their amplification products are shown in Fig. 1. The concentration of purified amplimer was estimated by the intensity of its ethidium-bromide-stained band on a 1% agarose gel, and 6–8 ng/µL (1 ng/µL for each 100 bp) of template and 3.2 pMol/µL of primer were used in each sequencing reaction.

View larger version (51K): [in this window] [in a new window]   Figure 1. Strategy for mutation analysis. The structure of the human amelogenin gene is shown at the top. The exons are blocks numbered 1 through 7. Below each exon is a bar corresponding to the region amplified and a number indicating the number of nucleotides in each PCR product. The DNA sequences of the primer pairs used to generate the exon-specific PCR amplification products, written in the 5' to 3' orientation, are shown below, along with the annealing temperature used in the amplifications, provided in the table at the bottom. The PCR reactions have a five-minute denaturation at 94°C, followed by 40–50 cycles each with denaturation at 94°C for 30 sec, primer annealing at 56–61°C (as shown in the table) for 30 sec, and product extension at 72°C for 40 sec. In the final cycle, the 72°C extension was for 5 min. PCR amplification products were purified by use of the QIAquick PCR Purification Kit (Qiagen Inc., Valencia, CA, USA), and are shown on a 1% agarose gel stained with ethidium bromide, in the center of the Fig.

Light and Scanning Electron Microscopy
Two naturally exfoliated primary cuspids and a primary mandibular central incisor were obtained from the proband and an affected sister with the p.M1T mutation for histological analysis of the enamel and dentin. Thin sections were cut with a diamond blade to thicknesses of approximately 120 µm and examined with light microscopy as previously described (Wright et al., 1993a). Samples for scanning electron microscopy were either fractured or cut, polished to a 0.25-µm finish, and etched for 60 sec with 0.07 M H₃PO₄ as previously described (Wright et al., 1993b).

	RESULTS

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Two kindreds afflicted with X-linked AI were recruited for mutation analysis. In both families, the proband was a young girl in the mixed-dentition stage of development. Using newly designed PCR primer pairs and genomic DNA template from affected members, we generated exon-specific AMELX amplification products ranging from 575 to 775 bp in length (Fig. 1), which were characterized by DNA sequencing. Different exon 2 mutations were identified in the two families, and these mutations correlated with affection status.

Family 1 is a kindred in which the AI affection status, based upon the family history, is known for 5 generations (Fig. 2). Eleven members of this kindred were recruited, which included six unaffected (four females, two males) and five affected (four females, one male) members. Genomic DNA was amplified and characterized from an affected male (IV-2). The seven AMELX amplification products varied from the AMELX reference sequence (AY040206) in exon 2, which altered the amelogenin translation initiation codon, and in exon 6, which did not alter the deduced amino acid sequence. Single-stranded conformational polymorphism (SSCP) analysis showed that the exon 2 mutation was present in all of the five affected, and in none of the six unaffected, family members (Fig. 2). Based upon the amelogenin genomic (AY040206), cDNA, and deduced amino acid (AF436849) reference sequences, and the published standardized nomenclature for AI mutations (Hart et al., 2002), the start codon mutation in family 1 is described as g.2T>C for the gene, c.2T>C for the cDNA, and p.M1T for the protein. The polymorphism in exon 6 is g.3834C>T for the gene and g.261C>T for the cDNA.

View larger version (69K): [in this window] [in a new window]   Figure 2. Genotype and phenotypes of AI families. Panels A through I are from family 1 (p.M1T): oral photograph of the proband (A); the pedigree (B); bitewing radiographs of the proband, showing the very thin enamel layer that is evident only radiographically on the cusp tips (C,D); DNA sequencing chromatograms (E–H) of exon 2 from an affected male member (IV-2) showing the mutation (Mut) that changed the ATG of the wild-type (Wt) start codon into an ACG, which is normally a threonine codon; and single-stranded conformational polymorphism (SSCP) analysis of exon 2, with arrowheads pointing to the extra band that correlates with affection status (I). Panels J through P are from family 2 (p.W4S): oral photographs of the proband (J, III-2) and her mother (K, II-2), who were both affected; the pedigree of family 2 (L); and DNA sequencing chromatograms from the proband, showing the mutation in the fourth codon of exon 2 (M-P), which changed the wild-type tryptophan codon (TGG) into a serine (TCG) codon.

Naturally exfoliated primary cuspids and a mandibular central incisor were obtained from girls having the p.M1T mutation (Fig. 3). Light microscopy of ground sections showed that the enamel layer is very thin, or about 1/4 the thickness of a wild-type control (Figs. 3A–3D). Scanning electron microscopy indicated that the thin enamel lacked a prismatic structure for the most part (Figs. 3E, 3F), although there were some areas that looked like they had an organized crystallite orientation that approached a normal prismatic pattern (Figs. 3G, 3H). The tooth surface was rough and pitted (Fig. 3I). The dentin appeared normal, with distinct dentinal tubules coursing from the DEJ pulpally (Figs. 3J, 3K).

View larger version (129K): [in this window] [in a new window]   Figure 3. Analysis of naturally exfoliated primary teeth from affected girls in family 1 (p.M1T). Ground sections of normal (A,C) and defective (B,D) teeth illustrate the relative thinness (1/4 of normal) of the enamel layer in the affected teeth. The enamel prism structure of the normal teeth is evident in scanning electron micrographs (E, bar = 100 µm), but is not evident, even at twice the magnification (F, bar = 100 µm), in affected teeth. At higher magnification, prism organization that only partially approaches that observed in normal enamel (G, bar = 10 µm) could be recognized in occasional areas (H, bar = 10 µm). To the unaided eye, the enamel surface of the affected teeth looked rough (I), which was due to the presence of pits along the enamel surface that varied in size from about 10 to 30 µm (F). The dentin appeared to be normal at low (J) and high (K, bar = 10 µm) magnifications, with well-defined dentinal tubules. Arrowheads indicate the DEJ.

The incisal edges of the anterior teeth on the proband showed developmentally prominent mammelons, which were apparently preserved by the anterior open bite. The affected mother reported having previously undergone orthodontic treatment for correction of an anterior open bite. The enamel, although thinner than normal, was not as thin as in family 1 and could be readily identified on radiographs as a continuous radiopaque layer covering the dentin. The underlying dentin appeared to show through the thin enamel covering, but the resulting yellowish shade was also not as strong as in family 1. Both affected females showed a pattern of alternative vertical bands of thin enamel and enamel of more normal thickness.

	DISCUSSION

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In this study, we have identified two AMELX mutations in exon 2 that cause X-linked AI. The first mutation disrupts the translation initiation codon (p.M1T); the second mutation changes the fourth amino acid in the signal peptide (p.W4S). One possible effect of the p.M1T mutation would be to block translation of amelogenin expressed from the defective mRNA transcripts (null mutation). On the other hand, translation might not be blocked, but rather shifted to the second ATG (encoding Met17), which is also encoded in exon 2 and is normally at the N-terminus of the secreted amelogenin protein. This second start codon is theoretically acceptable for translation initiation as adenosine is in the –3 position (Kozak, 1984), but would be a weak translation initiator relative to the normal start codon (Kozak, 1986). The effect of p.M1T, therefore, might be the expression of the secreted amelogenin protein intracellularly, but at lower levels than are normally secreted by wild-type cells. The p.W4S mutation in family 2 is in the signal peptide-coding region and might be expected to reduce translocation of the nascent amelogenin protein into the endoplasmic reticulum. Signal peptide prediction software (SignalP V2.0, at http://www.cbs.dtu.dk/services/SignalP/) predicted that the mutant (p.W4S) signal peptide sequence would not be greatly affected by the serine for tryptophan substitution (Nielsen et al., 1997). However, a mutation in the DSPP signal peptide-coding region was shown to reduce translocation of that protein greatly, despite a similar prediction by this software (Rajpar et al., 2002). The tryptophan mutated in family 2 is strictly conserved in every mammal for which sequence is known. This, and the finding that this mutation is associated with enamel hypoplasia in our kindred, suggests that the p.W4S mutation might reduce secretion of amelogenin protein, and cause some amelogenin protein fused to the defective signal peptide to be synthesized in the cytoplasm. This amelogenin protein might be expressed at higher levels than in family 1, but might be degraded more rapidly if protein folding is affected by the retained signal peptide. The intracellular expression of amelogenin might interfere with normal cell processes, making the dental phenotype a sum of the effects of cell pathology and a reduction of amelogenin protein in the matrix.

Pathologically thin, or hypoplastic, enamel is caused by a failure in crystal elongation, which occurs during the secretory stage of amelogenesis (Simmer and Fincham, 1995; Fincham et al., 1999). After the enamel crystals achieve their final length (and the enamel layer itself achieves its final thickness), the organic matrix separating individual enamel crystallites is degraded and re-absorbed. If the organic matrix is not properly removed, pathologically soft (hypomaturation) forms of AI result (Smith, 1998). In the four AI cases where a signal peptide mutation blocks amelogenin secretion, the defect appears to have affected the secretory stage only. In cases where a defective amelogenin protein is secreted, the mutant amelogenin protein may be resistant to degradation by enamel proteases and may not be thoroughly cleared from the matrix, resulting in a hypomaturation type of AI, which may produce a more noticeable Lyonization pattern (Collier et al., 1997; Li et al., 2003).

Clinically, females with X-linked AI often show vertical bands of apparently normal, translucent enamel alternating with thinner (hypoplastic) white opaque enamel. These vertical bands are believed to be an "X-inactivation pattern" or "Lyonization" pattern, due to the presence of alternating bands of ameloblasts secreting normal and defective amelogenin (Berkman and Singer, 1971; Witkop and Sauk, 1976). Phenotype variation in females heterozygous for X-linked genes can be caused by non-random X-chromosome inactivation (Sharp et al., 2000; Plenge et al., 2002). At the present time, there is no evidence that skewing of X-inactivation causes variations in the AI phenotype that might explain the apparent lack of a Lyonization pattern in family 1 with X-linked AI. The most common mechanism that skews X-inactivation is when a disproportionate number of cells show inactivation of the mutated over the wild-type X chromosome through cell selection, that is, cells expressing the mutant gene die or cannot divide as well as those expressing the wild-type gene (Lyon, 2002). In such cases, however, proliferative selection against cells expressing the abnormal gene to cells expressing the wild-type copy is expected to cause a more mild phenotype in the female than might occur in the absence of such selection. In our family 1, where the phenotype in females is severe, selection against cells expressing the mutant amelogenin gene (p.M1T) seems unlikely. In family 2, the comparatively mild phenotype is readily explained if the signal peptide mutation (p.W4S) only partially interfered with translocation into the endoplasmic reticulum (ER). Any amelogenin that did make it into the ER would be secreted as a perfectly normal amelogenin protein.

There are currently no data concerning the relative expression of amelogenin from the paternal and maternal X chromosomes in either normal or diseased individuals. Despite this, skewed X-inactivation patterns must be considered as a possible cause of phenotypic variation in X-linked AI. In the four kindreds showing amelogenin signal peptide mutations, the phenotype is remarkably consistent. Severe enamel hypoplasia with a slightly rough surface, exaggerated mammelons, or incisal chipping with an X-linked pattern of inheritance should arouse suspicion of a possible mutation in exon 2 of the AMELX. The presence or absence of an anterior open bite is not a consistent finding in the kindreds with an AMELX signal peptide mutation, and suggests that it is a secondary rather than a direct pleiotropic effect of the gene mutation.

	ACKNOWLEDGMENTS

 
This investigation was supported in part by the Foundation of the American Academy of Pediatric Dentistry, and by USPHS Research Grants DE12769, DE11301, and DE12879 from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 29892.

Received July 3, 2003; Last revision March 4, 2004; Accepted March 5, 2004

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This Article Abstract Figures Only Full Text (PDF) Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Kim, J.-W. Articles by Hu, J.C.-C. Search for Related Content PubMed PubMed Citation Articles by Kim, J.-W. Articles by Hu, J.C.-C.