HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Appendix 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 Google Scholar Google Scholar Articles by Kim, J.-W. Articles by Simmer, J.P. Search for Related Content PubMed PubMed Citation Articles by Kim, J.-W. Articles by Simmer, J.P.

Hereditary Dentin Defects

¹ Seoul National University, School of Dentistry Department of Pediatric Dentistry & Dental Research Institute, 28-2 Yongon-dong, Chongno-gu, Seoul, Korea 110-749; and
² Department of Biologic and Materials Science, University of Michigan School of Dentistry, Dental Research Lab, 1210 Eisenhower Place, Ann Arbor, MI 48108, USA

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
By the Shields classification, articulated over 30 years ago, inherited dentin defects are divided into 5 types: 3 types of dentinogenesis imperfecta (DGI), and 2 types of dentin dysplasia (DD). DGI type I is osteogenesis imperfecta (OI) with DGI. OI with DGI is caused, in most cases, by mutations in the 2 genes encoding type I collagen. Many genes are required to generate the enzymes that catalyze collagen’s diverse post-translational modifications and its assembly into fibers, fibrils, bundles, and networks. Rare inherited diseases of bone are caused by defects in these genes, and some are occasionally found to include DGI as a feature. Appreciation of the complicated genetic etiology of DGI associated with bony defects splintered the DGI type I description into a multitude of more precisely defined entities, all with their own designations. In contrast, DD-II, DGI-II, and DGI-III, each with its own pattern of inherited defects limited to the dentition, have been found to be caused by various defects in DSPP (dentin sialophosphoprotein), a gene encoding the major non-collagenous proteins of dentin. Only DD-I, an exceedingly rare condition featuring short, blunt roots with obliterated pulp chambers, remains untouched by the revolution in genetics, and its etiology is still a mystery. A major surprise in the characterization of genes underlying inherited dentin defects is the apparent lack of roles played by the genes encoding the less-abundant non-collagenous proteins in dentin, such as dentin matrix protein 1 (DMP1), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE), and secreted phosphoprotein-1, or osteopontin (SPP1, OPN). This review discusses the development of the dentin extracellular matrix in the context of its evolution, and discusses the phenotypes and clinical classifications of isolated hereditary defects of tooth dentin in the context of recent genetic data respecting their genetic etiologies.

KEY WORDS: dentin • dentin sialophosphoprotein • osteogenesis imperfecta • dentinogenesis imperfecta • dentin dysplasia

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
Dentin is the mineralized tissue constituting the body of a tooth, serving as a protective covering for the pulp and as a support for overlying enamel and cementum. On a weight basis, mature dentin is about 70% mineral, 20% organic matrix, and 10% water. Dentin is the product of specialized, end-differentiated, cells called odontoblasts. Odontoblasts comprise a sheet of columnar cells that line the pulpal surface of dentin and extend cell processes partly or all the way through dentin. Odontoblasts are intimately associated with the formation and maintenance of dentin, communicate with pulp afferent nerves, and serve as the first biological line of defense against environmental injury, such as in caries (Nanci, 2003). Our goal is to understand how normal dentin forms and functions. To achieve this goal, we are interested in the evolution of dentin and other mineralized tissues, how odontoblasts differentiate and control the expression and secretion of proteins, the composition and structural/functional properties of dentin extracellular matrix constituents, how odontoblasts monitor the extracellular matrix and respond to feedback, and, finally, how specific genetic defects lead to the observed patterns of inherited dental malformations. It is hoped that insights gained by improving our understanding in these areas will lead to improvements in the way we diagnose and treat pathologies affecting dentin, whether they arise from genetic or environmental factors, injury, or disease. Here we present a perspective and a review of the hereditary defects of tooth dentin that are classified under the designations of dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) (Shields et al., 1973).

	EVOLUTION AND DEVELOPMENT

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
In this section, we discuss development of the dentin extracellular matrix in the context of the evolution of extracellular matrices and biomineralization, to provide insights into the genetic etiologies of DGI and DD. The emergence of multicellular animals from single-celled organisms is associated with the expansion and enhancement of cell-signaling pathways, which include growth factors and receptors capable of transmembrane signal transduction, and homeotic transcription regulatory systems that mediate cell differentiation (David, 2001; Kaiser, 2001). Multicellularity requires strengthening of the linkages that bind cells together, and the construction of extracellular matrices (ECM) to provide structural integrity and to act as a substrate for cell adhesion, migration, and growth. Cells form an intimate relationship with the ECM they secrete (Humphries et al., 2004). Interactions between ECM components and membrane receptors and the sampling of the ECM by endocytosis are ways in which the ECM influences gene expression (Exposito et al., 2002). Fibrillar collagens are expressed by invertebrates and vertebrates and correlate with the emergence of multicellularity. In addition to collagen, extracellular matrices contain proteins, glycoproteins, and proteoglycans that commonly possess cell-binding and/or collagenbinding domains (Myllyharju and Kivirikko, 2001). These molecules organize collagen into fibrillar networks, appraise the cell of conditions in the ECM, and mediate signals that stimulate cellular responses to external stimuli. Besides collagen, hyaluronan is an important carbohydrate polymer of unbranched repeating disaccharide units that is able to bind cell receptors and connect proteins with glycan attachments into proteoglycan assemblies that are major structural and functional constituents of extracellular matrices. The evolution of complex and dynamic extracellular matrices occurred long before the advent of biomineralization. Molecular-clock analyses estimate that invertebrates diverged from chordates between one billion (Wray et al., 1996) and 615 million years ago (Peterson et al., 2004), indicating that collagen-based extracellular matrices existed by that time. Biomineralization of extracellular matrices evolved independently in many different taxa (Knoll, 2003). The earliest fossil evidence of mineralization in vertebrates is pharyngeal tooth-like structures (conodonts) from jawless fish that appear in the fossil record at ~ 540 million years ago (mya), but these organisms are believed to have diverged already from the line leading to tetrapods. The jawless fish (pteraspidomorphs) with dermal armor (~ 470 mya) are more likely inventors of biomineralization in the line ancestral to jawed vertebrates (Kawasaki et al., 2004), suggesting that collagen-based extracellular matrices evolved for tens to hundreds of millions of years prior to the onset of biomineralization. The major inference from the evolutionary perspective is that the biomineralization of bone and dentin is built upon an organic matrix that is involved in many important functions and interactions that are necessary for proper assembly and functioning of the matrix, but are not necessarily also involved in the deposition of mineral. The biomineralization of vertebrate extracellular matrices evolved through a more recent series of gene duplications and the origin or expansion of the secretory calcium-binding phosphoprotein (SCPP) family from the 5' region of the SPARC (secreted protein, acidic and rich in cysteine) gene (Delgado et al., 2001). The human SCPP family is comprised mainly of a cluster of genes on chromosome 4 that encode the major non-collagenous extracellular matrix proteins of bone, dentin, and enamel, as well as proteins secreted in milk and saliva (Kawasaki and Weiss, 2003, 2006). SIBLINGs (small integrin-binding ligand N-linked glycoproteins) are a subfamily of 5 SCPP genes involved in bone and dentin formation (Fisher and Fedarko, 2003), and are the primary candidate genes for isolated inherited dentin defects: dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE), and secreted phosphoprotein-1, or osteopontin (SPP1, OPN). In humans, the SIBLING genes form a cluster on chromosome 4q21–q25 (Fig. 1). Core-binding factor a1 (Cbfa1) is a transcription factor required for osteoblast and chondrocyte maturation that regulates the expression of the SIBLINGs and other genes. The Cbfa1^–/– knockout mice lack skeletal mineralization and die at birth (Komori et al., 1997).

View larger version (24K): [in this window] [in a new window]   Figure 1. SIBLING genes on human chromosome 4. Key: Dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE), secreted phosphoprotein-1 (SPP1).

	CLASSIFICATION OF INHERITED DENTIN DEFECTS

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

	SUMMARY OF THE SHIELDS CLASSIFICATION

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
DGI-I
This is the dental phenotype in persons afflicted with OI. The teeth show marked discoloration and attrition in both the deciduous and permanent dentitions. Pulpal obliteration occurs soon after eruption or prior to tooth eruption. The degree of expressivity is variable, even within a single individual, ranging from total pulpal obliteration to normal dentin.

DGI-II
This has many clinical and radiographic similarities to DGI-I, but penetrance is almost complete, and expressivity is much more consistent within a family when compared with that of DGI-I. Penetrance refers to how consistently a trait is observed, while expressivity refers to how severe a trait is when it is observed.

DGI-III
This was first found in the Brandywine tri-racial isolate from southern Maryland and Washington, DC. The "Brandywine isolate" is an inbred population of mixed Caucasian, Black, and Amerindian individuals in the USA. In coloration and shape, the teeth appear somewhat variable, as in DGI-I and DGI-II, but unlike the latter 2 traits, multiple pulp exposures are observed in the deciduous teeth. Radiographically, the deciduous teeth show considerable variation in appearance, ranging from pulpal obliteration, to normal, even to shell teeth. (Shell teeth have enlarged pulp chambers surrounded by only a thin layer of dentin.)

DD-I
The clinical crowns of both permanent and deciduous teeth are of normal shape, form, and color in most cases, but radiologically the teeth have short roots with a crescent-shaped pulpal remnant parallel to the cemento-enamel junction in the permanent dentition, and total pulpal obliteration in the deciduous dentition. There are usually numerous periapical radiolucencies in non-carious teeth.

DD-II
The deciduous teeth have features of DGI-II. The permanent teeth are of normal shape, form, and color in most cases, although the pulp cavities of permanent teeth show a thistle-tube deformity and commonly contain pulp stones. The root length is normal, and frequent periapical radiolucencies are not observed. In some cases, features characteristic of DGI-II are observed, such as bulbous crowns with cervical constriction, mild discoloration, and pulp obliteration (Shields et al., 1973; Ranta et al., 1990; Brenneise and Conway, 1999).

In human populations, there exists a broad spectrum of inherited dentin malformations. Shields’ classification attempted to compartmentalize this phenotypic variation into groups (Fig. 2). It was hoped that as additional kindreds with inherited dentin defects were characterized, their pathological features would sort relatively unambiguously into a single category, and that each category might share a common genetic etiology. These hopes have not been realized. Bulbous crowns with marked cervical constriction are not always restricted to DGI-II, thistle-tube pulp chambers are not observed only in DD-II, and wide pulp chambers and multiple pulp exposures are not limited to DGI-III (Levin et al., 1983; Clergeau-Guerithault and Jasmin, 1985). Perhaps most importantly, the distinguishing dental phenotypes of more than one type are commonly observed in different affected individuals in a single kindred (Heimler et al., 1985; Witkop, 1989). DD-II, DGI-II, and DGI-III may represent increasing levels of severity of a single disease (Beattie et al., 2006).

View larger version (52K): [in this window] [in a new window]   Figure 2. Isolated inherited dentin defects. Primary dentition of a person with DGI-II (top). Bitewing radiographs show pulp obliteration in the molars. Primary dentition of a person with DGI-III (middle). Radiograph shows widened pulp and root canals. Several teeth have abscesses following pulp exposure due to rapid attrition. Permanent dentition of a person with DD-II (bottom). Note the near-normal color of the teeth. The pulp chambers are smaller than normal (becoming obliterated prematurely).

	DENTINOGENESIS IMPERFECTA TYPE I (DGI-I)

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

OI is generally classified into 4 clinical types, although 3 additional types have been added, to include distinct features (Rauch and Glorieux, 2004). Mild forms of OI are usually caused by a premature stop codon or deletion of a single COL1A1 allele, which reduces the amount of normal type I collagen. Severe forms are caused by dominant-negative mutations in COL1A1 or COL1A2 that lead to structural defects in the assembled collagen fibril (Gajko-Galicka, 2002); however, genotype-phenotype correlations are often complex and unpredictable (Roughley et al., 2003), and OI is found in individuals with no apparent defects in the type I collagen genes (Rauch and Glorieux, 2004). Genetic heterogeneity in the etiology of osteogenesis imperfecta is established, since homozygous OI unlinked to type I collagen genes (Aitchison et al., 1988) was demonstrated, and OI type VII was linked to chromosome 3p22–24 (Labuda et al., 2002). Recently, a gene defect in the mouse osteogenesis and dentinogenesis imperfecta model, fragilitas ossium (fro), was identified in the gene encoding neutral sphingomyelin phosphodiesterase 3 (Smpd3) (Aubin et al., 2005). While OI with DGI (OI/DGI) is usually associated with collagen-I defects, the clinical expression and genetic etiology of OI/DGI are complex.

Collagen plays non-identical roles in bone and dentin, since the severity of the dentin and bone defects displayed by individuals with defined collagen mutations varies over a wide range (O’Connell and Marini, 1999). Some persons with OI displaying obvious DGI show no detectable bone phenotype (Pallos et al., 2001). In contrast, about half of all OI cases show no obvious clinical signs of DGI. In some OI cases, the DGI phenotype is not clinically evident, but can be detected radiologically (Lund et al., 1998). In other cases, the DGI is discovered only by histologic examination (Malmgren and Norgren, 2002), and then, the histological appearance of the dysplastic dentin is often less severe in the OI persons having clinical or radiological signs of DGI compared with those who do not (Malmgren and Lindskog, 2003).

Mild DGI has been associated with Bruck syndrome 1 (OI with congenital joint contractures, MIM %259450), an autosomal-recessive disorder (Brenner et al., 1993). Bruck syndrome 1 mapped to 17p12 region at the site of the gene encoding bone telopeptide lysyl hydroxylase (Bank et al., 1999). Bruck syndrome 2 (MIM #609220) maps to 3q23–q24 and is caused by mutations in the lysyl hydroxylase 2 gene (PLOD2) (van der Slot et al., 2003).

	DGI IN SYNDROMES OTHER THAN OI

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
The inclusion of DGI-I in Shields’ classification is unfortunate. DGI-I is an example of syndromic DGI (where the dentin defects are not the most predominant or consistent manifestation in most kindreds). All of the other inherited dentin defects in Shields’ classification are isolated (dentin defects are the predominant and only consistent manifestation). Increasingly, the DGI phenotype is recognized as a variable feature in many syndromes.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of generalized connective tissue disorders, the major features of which are tissue fragility, skin extensibility, and joint hypermobility (Uitto, 2005). Some forms of EDS have dental phenotypes such as dysplastic dentin and obliterated pulp chambers (Barabas, 1969), dental features mimicking DD-I (Pope et al., 1992), and characteristic DGI-II with variable expressivity (Komorowska et al., 1989). EDS has a wide phenotypic spectrum, consisting of 6 major classification types that can be caused by molecular defects in types I, III, and V collagen, tenascin-X, and 2 collagen-modifying enzymes (lysyl hydroxylase and procollagen N-peptidase) (Mao and Bristow, 2001; Schalkwijk et al., 2001).

Goldblatt syndrome (MIM 184260) is a form of spondylometaphyseal dysplasia with joint laxity and DGI. The deciduous teeth display typical DGI, but the permanent teeth appear normal. Aberrant mobility of type II collagen chains by gel electrophoresis suggested a point mutation in COL2A1 (12q13) (Bonaventure et al., 1992).

Schimke immuno-osseous dysplasia (SIOD, MIM #242900), an autosomal-recessive disorder, is characterized by a combination of spondylo-epiphyseal dysplasia, progressive renal disease, and lymphopenia with defective cellular immunity (Saraiva et al., 1999). A person with this disorder has characteristic DGI features, such as a grey-yellowish discoloration of the dentin, bulbous crowns with a marked cervical constriction, and small or obliterated pulp chambers (da Fonseca, 2000). Recently, SIOD was linked to mutations in SMARCAL1, encoding a chromatin remodeling protein (Boerkoel et al., 2002).

There are also sporadic reports of persons displaying DGI as part of a larger syndrome, but the genetic etiology remains unknown (Beighton, 1981). Opalescent teeth have been reported in a person having skeletal dysplasia with disproportionate short stature, short neck, broad chest, kyphosis, and protruding abdomen (Kantaputra, 2001), and in two siblings with microcephalic osteodysplastic primordial dwarfism (Kantaputra, 2002). The deciduous and permanent teeth were equally opalescent, and the roots were extremely short and tapered, or rootless.

A family with an unusual pattern of skeletal malformations resembling OI has been reported (Moog et al., 1999). Two affected siblings had OI-like features (bone fragility, wormian bone, and DGI), but normal collagen findings. In this case, the unaffected mother also had some features of DGI, so either the DGI in this family might be independent of the skeletal dysplasia, or the syndrome has extremely variable expression and the mother is indeed affected.

Recently, two brothers born of consanguineous parents had DGI, delayed tooth eruption, mild mental retardation, proportionate short stature, sensorineural hearing loss, and dysmorphic faces. No mutation in type I collagen was identified, and the mode of inheritance was proposed as autosomal-recessive (Cauwels et al., 2005).

	DENTINOGENESIS IMPERFECTA TYPE II (DGI-II)

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
DGI-II is one of the most common dominantly inherited disorders and affects approximately one person in every 8000. Genetic analyses linked DGI-II (Ball et al., 1982; Aplin et al., 1999), DGI-III (Boughman et al., 1986), and DD-II (Dean et al., 1997) to the chromosome 4q21 region, making the SIBLING family the prime candidate genes for these disorders. Defects in the DSPP gene can cause DGI-II (Xiao et al., 2001; Zhang et al., 2001; Kim et al., 2004; Malmgren et al., 2004), DGI-III (Dong et al., 2005; Kim et al., 2005), and DD-II (Rajpar et al., 2002). While there are other candidate genes for hereditary dentin defects (Ye et al., 2004), no disease-causing mutations outside of the DSPP gene have yet been identified (Table). The DSPP gene structure showing the positions of known disease-causing mutations is provided in Fig. 3.

View larger version (10K): [in this window] [in a new window]   Figure 3. Human DSPP gene structure and known disease-causing mutations. The boxes are exons, and the lines are introns. The lines above the gene diagram mark the positions of known disease-causing mutations in DSPP, which are: p.Y6D, p.A15D, p.P17T, Splice IVS2–3C>G, p.V18F, p.Q45X, Splice IVS3+1G>A, p.R68W, and p.del:1160–1171/p.Ins1198–1199. The amino acids corresponding to the porcine DSPP domain structure (Signal peptide-DSP-DGP-DPP) are shown in parentheses. Much of the human DPP coding region in exon 5 is highly redundant and cannot be screened for mutations.

	DENTINOGENESIS IMPERFECTA TYPE III (DGI-III)

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
The 2 main features (multiple pulp exposures and shell teeth) used to distinguish DGI-III from DGI-II are not unique to DGI-III. The pulp chambers in DGI-II are sometimes abnormally wide initially (shell teeth), but they progressively obliterate (Heimler et al., 1985; Ranta et al., 1993; Tanaka and Murakami, 1998; Sapir and Shapira, 2001). Even in the Brandywine isolate (the DGI-III prototype), the phenotype of shell teeth was described only in young children (Witkop, 1975). The similarities between DGI-II and DGI-III extend beyond the phenotype to the genotype: The same DSPP mutation (c.52GT, p.V18F) manifested as DGI-II and DGI-III in different families (Kim et al., 2005), and the genetic defects underlying the original Brandywine phenotype are in DSPP (Dong et al., 2005). The Dspp^–/– mouse teeth displayed relatively severe deficiencies in root dentin formation, similar to those in the human DGI-III phenotype (Sreenath et al., 2003).

	DENTIN DYSPLASIA TYPE I (DD-I)

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
DD-I is a rare anomaly of unknown etiology that affects approximately one patient in every 100,000. Several DD-I kindreds showed an autosomal-dominant mode of inheritance. It is not known if DD-I is another allelic disorder of the DSPP gene, or a mixed phenotype. DD-I, DD-II, and DGI-II have been observed within a single family (Graham et al., 1965) or single affected individual (Ciola et al., 1978; Tidwell and Cummingham, 1979; Diamond, 1989).

	DENTIN DYSPLASIA TYPE II (DD-II)

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
A mutation in the DSPP signal peptide codon (c.16TG, p.Y6D) was identified in a DD-II family (Rajpar et al., 2002). The effect of the mutation was a reduction (by less than 50%) of the amount of DSPP secreted into the forming dentin matrix, but the secreted protein was entirely normal. Since some of the mutations underlying DGI-II resulted in no DSPP expression from the mutant allele (a 50% reduction), the genetic data were consistent with the interpretation that the DD-II and DGI-II phenotypes are mild and severe forms of the same disease.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
In humans, there are 27 different types of collagen, expressed from 42 different collagen genes (Myllyharju and Kivirikko, 2004). Type I collagen constitutes 85–90% of the dentin organic matrix (Linde et al., 1980), and is the major protein in bone. The triple-helical (3D) structure of collagen was determined by fiber diffraction over 50 years ago (Rich and Crick, 1955), and its many post-translational modifications have been characterized (Viguet-Carrin et al., 2006). The abundance of collagen in bone and dentin and the elaborate biochemistry involved in its synthesis are evident in the diverse etiology and clinical manifestations of inherited defects involving both bone and dentin. In these disorders, bone is more sensitive to collagen defects than is dentin, and the bony defects are generally a more consistent phenotypic feature than are the dentin defects. Because bone defects are the more predominant phenotype in OI and related diseases, these disorders are more properly included in classification systems other than the DGI-I designation in the Shields’ classification.

The observation that bone is more sensitive to type I collagen defects than is dentin remains unexplained. Perhaps it relates to bone being a critical element of the hormonally regulated calcium and phosphate homeostasis system (Costanzo, 1998), or to the capacity of bone for regeneration and repair. Part of the reason may relate to differences between bone and dentin in the way collagen binds to, and is organized by, non-collagenous proteins.

The most abundant non-collagenous proteins in dentin are the DSPP-derived proteins (MacDougall et al., 1997). Shortly after DSPP is synthesized by odontoblasts, it is cleaved into 3 structural/functional domains: dentin sialoprotein (DSP) (Ritchie et al., 1994), dentin glycoprotein (DGP) (Yamakoshi et al., 2005b), and dentin phosphoprotein (DPP) (Ritchie and Wang, 1996). In contrast to what is known about collagen structurally, the post-translational modifications of DSPP-derived proteins (excepting DGP) have been only poorly characterized (Qin et al., 2004), and their 3-D structures are completely unknown. It was only recently demonstrated that DSP is a proteoglycan capable of forming covalent dimers (Yamakoshi et al., 2005a), and that DMP1 is a proteoglycan (Qin et al., 2006). Targeted gene knockouts in mice have demonstrated that at least 5 genes encoding proteoglycans contribute to dentin formation: Dspp (Sreenath et al., 2003), Dmp1 (Ye et al., 2004), fibromodulin (Fmod) (Goldberg et al., 2006), and biglycan (Bgn) and decorin (Dcn) (Goldberg et al., 2005). All of these proteoglycans bind collagen. DSPP is the only one of these genes that is primarily dedicated to dentin formation and has been shown to be part of the etiology of isolated dentin defects.

Genetic studies prove that DSPP is critical for proper dentin formation. It is apparent that DSPP-derived proteins play a role beyond biomineralization, and probably serve several important functions. Inferences about the functions of DSPP based upon the nature of DGI and DD phenotypes are limited, because of the possibility of secondary effects. The obliteration of pulp by the accelerated deposition of secondary dentin, for instance, could be the consequence of odontoblasts responding to a deficiency in the matrix or weakness of the dentin. In the Dspp knockout mice, biglycan and decorin were increased in the widened predentin zone. How much of the Dspp^–/– phenotype is caused by these secondary changes?

Since isolated inherited dentin defects are divided into 4 types in the Shields’ classification, it is surprising that the early results of mutational analyses have identified mutations only in DSPP, and in none of the other 4 SIBLING genes. To date, 8 different disease-causing DSPP mutations have been identified in the 5' region, up to and including the codon for Arg⁶⁸ in exon 4. In our analyses of nine kindreds with inherited dentin defects, five showed disease-causing mutations in the 5' coding region of DSPP. Disease-causing mutations in the 3' coding region of DSPP might have caused the disease in some or all of the other kindreds. Currently, the DPP coding region cannot be analyzed for mutations because of its high sequence redundancy. Therefore, the initial findings of genetic studies seeking to understand the genetic causes of isolated dentin defects indicate that DSPP mutations play the predominant etiological role, but contributions by the other SIBLING genes cannot be ruled out.

The human DSPP cDNA (Gu et al., 1998) and genomic (#AF163151; 9944 bp) (Gu et al., 2000) sequences have been reported. Based upon the human genomic sequence, a DSPP reference sequence was assembled (#NM_014208; 4187 bp). Also in the databases are the human chromosome 4 contig (#NT_016354.17) and alternate assembly (#NT_086651.1). These independently determined human DSPP sequences show significant variation in the DPP coding region (exon 5), so that the wild-type human DPP sequence is still unknown. (An alignment of the DSPP reference sequence against other human DSPP sequences from NCBI is provided in the APPENDIX.) These sequence differences lead us to suspect that the DPP coding region is highly polymorphic in humans. Technical advances in our ability to perform sequence analyses in the DPP coding region are needed, along with knowledge of the normal range of DSPP sequence variations, before the role played by DPP mutations in the etiology of inherited dentin defects can be elucidated.

In summary, great advances are being made in our understanding of how mineralized tissues evolved over the long course of time. The growth factors and homeotic transcription factors that control tooth development and cell differentiation are being identified, and their contributions defined. The macromolecular components of mineralizing extracellular matrices have been isolated, and their structures and functions are being profitably investigated. The genetic etiologies of syndromic and isolated inherited dentin defects are being described. These exciting advances are steadily improving our understanding of normal and pathological tooth formation, and are inspiring new diagnostic and therapeutic innovations to improve our oral health.

	ACKNOWLEDGMENTS

 
This work was supported by a grant (A060010) from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea, and by NIDCR grants DE12769 and DE15846.

	FOOTNOTES

 
A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.

Received June 2, 2006; Accepted October 19, 2006

	REFERENCES

TOP ABSTRACT INTRODUCTION EVOLUTION AND DEVELOPMENT CLASSIFICATION OF INHERITED... SUMMARY OF THE SHIELDS... DENTINOGENESIS IMPERFECTA TYPE I... DGI IN SYNDROMES OTHER... DENTINOGENESIS IMPERFECTA TYPE... DENTINOGENESIS IMPERFECTA TYPE... DENTIN DYSPLASIA TYPE I... DENTIN DYSPLASIA TYPE II... DISCUSSION REFERENCES

 
Aitchison K, Ogilvie D, Honeyman M, Thompson E, Sykes B (1988). Homozygous osteogenesis imperfecta unlinked to collagen I genes. Hum Genet 78:233–236.[ISI][Medline]

Aplin HM, Hirst KL, Dixon MJ (1999). Refinement of the dentinogenesis imperfecta type II locus to an interval of less than 2 centiMorgans at chromosome 4q21 and the creation of a yeast artificial chromosome contig of the critical region. J Dent Res 78:1270–1276.[Abstract/Free Full Text]

Aubin I, Adams CP, Opsahl S, Septier D, Bishop CE, Auge N, et al. (2005). A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nat Genet 37:803–805.[ISI][Medline]

Ball SP, Cook PJ, Mars M, Buckton KE (1982). Linkage between dentinogenesis imperfecta and Gc. Ann Hum Genet 46:35–40.[ISI][Medline]

Bank RA, Robins SP, Wijmenga C, Breslau-Siderius LJ, Bardoel AF, van der Sluijs HA, et al. (1999). Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17. Proc Natl Acad Sci USA 96:1054–1058.[Abstract/Free Full Text]

Barabas GM (1969). The Ehlers-Danlos syndrome. Abnormalities of the enamel, dentine, cementum and the dental pulp: an histological examination of 13 teeth from 6 patients. Br Dent J 126:509–515.[Medline]

Beattie ML, Kim JW, Gong SG, Murdoch-Kinch CA, Simmer JP, Hu JC (2006). Phenotypic variation in dentinogenesis imperfecta/dentin dysplasia linked to 4q21. J Dent Res 85:329–333.[Abstract/Free Full Text]

Beighton P (1981). Familial dentinogenesis imperfecta, blue sclerae, and wormian bones without fractures: another type of osteogenesis imperfecta? J Med Genet 18:124–128.[Abstract]

Bixler D (1976). Heritable disorders affecting dentin. In: Oral facial genetics. Stewart RE, Prescott GH, editors. St. Louis: C.V. Mosby Co., pp. 227–261.

Boerkoel CF, Takashima H, John J, Yan J, Stankiewicz P, Rosenbarker L, et al. (2002). Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat Genet 30:215–220.[ISI][Medline]

Bonaventure J, Stanescu R, Stanescu V, Allain JC, Muriel MP, Ginisty D, et al. (1992). Type II collagen defect in two sibs with the Goldblatt syndrome, a chondrodysplasia with dentinogenesis imperfecta, and joint laxity. Am J Med Genet 44:738–753.[ISI][Medline]

Boughman JA, Halloran SL, Roulston D, Schwartz S, Suzuki JB, Weitkamp LR, et al. (1986). An autosomal-dominant form of juvenile periodontitis: its localization to chromosome 4 and linkage to dentinogenesis imperfecta and Gc. J Craniofac Genet Dev Biol 6:341–350.[ISI][Medline]

Brenneise CV, Conway KR (1999). Dentin dysplasia, type II: report of 2 new families and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:752–755.[ISI][Medline]

Brenner RE, Vetter U, Stoss H, Muller PK, Teller WM (1993). Defective collagen fibril formation and mineralization in osteogenesis imperfecta with congenital joint contractures (Bruck syndrome). Eur J Pediatr 152:505–508.[ISI][Medline]

Cauwels RG, De Coster PJ, Mortier GR, Marks LA, Martens LC (2005). Dentinogenesis imperfecta associated with short stature, hearing loss and mental retardation: a new syndrome with autosomal recessive inheritance? J Oral Pathol Med 34:444–446.[ISI][Medline]

Ciola B, Bahn SL, Goviea GL (1978). Radiographic manifestations of an unusual combination Types I and Type II dentin dysplasia. Oral Surg Oral Med Oral Pathol 45:317–322.[ISI][Medline]

Clergeau-Guerithault S, Jasmin JR (1985). Dentinogenesis imperfecta type III with enamel and cementum defects. Oral Surg Oral Med Oral Pathol 59:505–510.[ISI][Medline]

Costanzo LS (1998). Regulation of calcium and phosphate homeostasis. Adv Physiol Educ 275:S206–S216.[Free Full Text]

da Fonseca MA (2000). Dental findings in the Schimke immuno-osseous dysplasia. Am J Med Genet 93:158–160.[ISI][Medline]

David JR (2001). Evolution and development: some insights from evolutionary theory. An Acad Bras Cienc 73:385–395.[ISI][Medline]

Dean JA, Hartsfield JK Jr, Wright JT, Hart TC (1997). Dentin dysplasia, type II linkage to chromosome 4q. J Craniofac Genet Dev Biol 17:172–177.[ISI][Medline]

Delgado S, Casane D, Bonnaud L, Laurin M, Sire JY, Girondot M (2001). Molecular evidence for precambrian origin of amelogenin, the major protein of vertebrate enamel. Mol Biol Evol 18:2146–2153.[Abstract/Free Full Text]

Diamond O (1989). Dentin dysplasia type II: report of case. ASDC J Dent Child 56:310–312.[Medline]

Dong J, Gu T, Jeffords L, MacDougall M (2005). Dentin phosphoprotein compound mutation in dentin sialophosphoprotein causes dentinogenesis imperfecta type III. Am J Med Genet A 132:305–309.[Medline]

Exposito JY, Cluzel C, Garrone R, Lethias C (2002). Evolution of collagens. Anat Rec 268:302–316.[Medline]

Fisher LW, Fedarko NS (2003). Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res 44(Suppl 1):33–40.[Medline]

Gajko-Galicka A (2002). Mutations in type I collagen genes resulting in osteogenesis imperfecta in humans. Acta Biochim Pol 49:433–441.[ISI][Medline]

Goldberg M, Septier D, Rapoport O, Iozzo RV, Young MF, Ameye LG (2005). Targeted disruption of two small leucine-rich proteoglycans, biglycan and decorin, excerpts divergent effects on enamel and dentin formation. Calcif Tissue Int 77:297–310.[ISI][Medline]

Goldberg M, Septier D, Oldberg A, Young MF, Ameye LG (2006). Fibromodulin-deficient mice display impaired collagen fibrillogenesis in predentin as well as altered dentin mineralization and enamel formation. J Histochem Cytochem 54:525–537.[Abstract/Free Full Text]

Graham WL, Harley JB, Alberico C, Kelln EE (1965). Absent lamina dura associated with a developmental dentin abnormality. A family study. Arch Intern Med 116:837–841.[ISI][Medline]

Gray PH (1970). A case of osteogenesis imperfecta, associated with dentinogenesis imperfecta, dating from antiquity. Clin Radiol 21:106–108.[Medline]

Gu K, Chang SR, Slaven MS, Clarkson BH, Rutherford RB, Ritchie HH (1998). Human dentin phosphophoryn nucleotide and amino acid sequence. Eur J Oral Sci 106:1043–1047.[ISI][Medline]

Gu K, Chang S, Ritchie HH, Clarkson BH, Rutherford RB (2000). Molecular cloning of a human dentin sialophosphoprotein gene. Eur J Oral Sci 108:35–42.[ISI][Medline]

Heimler A, Sciubba J, Lieber E, Kamen S (1985). An unusual presentation of opalescent dentin and Brandywine isolate hereditary opalescent dentin in an Ashkenazic Jewish family. Oral Surg Oral Med Oral Pathol 59:608–615.[ISI][Medline]

Hodge HC, Lose GB, Finn SB, Gachet FS, Bassett SH, Robb RC, et al. (1936). Correlated clinical and structural study of hereditary opalescent dentin (abstract). J Dent Res 15:316–317.

Humphries MJ, Travis MA, Clark K, Mould AP (2004). Mechanisms of integration of cells and extracellular matrices by integrins. Biochem Soc Trans 32(Pt 5):822–825.[ISI][Medline]

Kaiser D (2001). Building a multicellular organism. Annu Rev Genet 35:103–123.[ISI][Medline]

Kantaputra PN (2001). A newly recognized syndrome of skeletal dysplasia with opalescent and rootless teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92:303–307.[ISI][Medline]

Kantaputra PN (2002). Apparently new osteodysplastic and primordial short stature with severe microdontia, opalescent teeth, and rootless molars in two siblings. Am J Med Genet 111:420–428.[ISI][Medline]

Kawasaki K, Weiss KM (2003). Mineralized tissue and vertebrate evolution: the secretory calcium-binding phosphoprotein gene cluster. Proc Natl Acad Sci USA 100:4060–4065.[Abstract/Free Full Text]

Kawasaki K, Suzuki T, Weiss KM (2004). Genetic basis for the evolution of vertebrate mineralized tissue. Proc Natl Acad Sci USA 101:11356–11361.[Abstract/Free Full Text]

Kim JW, Nam SH, Jang KT, Lee SH, Kim CC, Hahn SH, et al. (2004). A novel splice acceptor mutation in the DSPP gene causing dentinogenesis imperfecta type II. Hum Genet 115:248–254.[ISI][Medline]

Kim JW, Hu JC, Lee JI, Moon SK, Kim YJ, Jang KT, et al. (2005). Mutational hot spot in the DSPP gene causing dentinogenesis imperfecta type II. Hum Genet 116:186–191.[ISI][Medline]

Knoll AH (2003). Biomineralization and evolutionary history. Rev Min Geochem 54:329–356.[Free Full Text]

Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764.[ISI][Medline]

Komorowska A, Rozynkowa D, Lee KW, Renouf DV, Nicholls AC, MacKenzie J, et al. (1989). A Polish variant of isolated dentinogenesis imperfecta with a generalised connective tissue defect. Br Dent J 167:239–243.[ISI][Medline]

Kuurila K, Grenman R, Johansson R, Kaitila I (2000). Hearing loss in children with osteogenesis imperfecta. Eur J Pediatr 159:515–519.[ISI][Medline]

Labuda M, Morissette J, Ward LM, Rauch F, Lalic L, Roughley PJ, et al. (2002). Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone 31:19–25.[Medline]

Lawrence HP, Garcia RI, Essick GK, Hawkins R, Krall EA, Spiro A 3rd, et al. (2001). A longitudinal study of the association between tooth loss and age-related hearing loss. Spec Care Dentist 21:129–140.[Medline]

Levin LS, Leaf SH, Jelmini RJ, Rose JJ, Rosenbaum KN (1983). Dentinogenesis imperfecta in the Brandywine isolate (DI type III): clinical, radiologic, and scanning electron microscopic studies of the dentition. Oral Surg Oral Med Oral Pathol 56:267–274.[ISI][Medline]

Linde A, Bhown M, Butler WT (1980). Noncollagenous proteins of dentin. A re-examination of proteins from rat incisor dentin utilizing techniques to avoid artifacts. J Biol Chem 255:5931–5942.[Abstract/Free Full Text]

Lund AM, Jensen BL, Nielsen LA, Skovby F (1998). Dental manifestations of osteogenesis imperfecta and abnormalities of collagen I metabolism. J Craniofac Genet Dev Biol 18:30–37.[ISI][Medline]

MacDougall M, Simmons D, Luan X, Nydegger J, Feng J, Gu TT (1997). Dentin phosphoprotein and dentin sialoprotein are cleavage products expressed from a single transcript coded by a gene on human chromosome 4. Dentin phosphoprotein DNA sequence determination. J Biol Chem 272:835–842.[Abstract/Free Full Text]

Malmgren B, Lindskog S (2003). Assessment of dysplastic dentin in osteogenesis imperfecta and dentinogenesis imperfecta. Acta Odontol Scand 61:72–80.[Medline]

Malmgren B, Norgren S (2002). Dental aberrations in children and adolescents with osteogenesis imperfecta. Acta Odontol Scand 60:65–71.[ISI][Medline]

Malmgren B, Lindskog S, Elgadi A, Norgren S (2004). Clinical, histopathologic, and genetic investigation in two large families with dentinogenesis imperfecta type II. Hum Genet 114:491–498.[ISI][Medline]

Mao JR, Bristow J (2001). The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest 107:1063–1069.[ISI][Medline]

Moog U, Maroteaux P, Schrander-Stumpel CT, van Ooij A, Schrander JJ, Fryns JP (1999). Two sibs with an unusual pattern of skeletal malformations resembling osteogenesis imperfecta: a new type of skeletal dysplasia? J Med Genet 36:856–858.[Abstract/Free Full Text]

Myllyharju J, Kivirikko KI (2001). Collagens and collagen-related diseases. Ann Med 33:7–21.[ISI][Medline]

Myllyharju J, Kivirikko KI (2004). Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 20:33–43.[ISI][Medline]

Nagasaka H, Matsukubo T, Takaesu Y, Kobayashi Y, Sato T, Ishikawa T (2002). Changes and equalization in hearing level induced by dental treatment and instruction in bilaterally equalized chewing: a clinical report. Bull Tokyo Dent Coll 43:243–250.[Medline]

Nanci A (2003). Dentin-pulp complex. In: Ten Cate’s oral histology development, structure, and function. 6th ed. Nanci A, editor. St. Louis, MO, USA: Mosby, pp. 192–239.

O’Connell AC, Marini JC (1999). Evaluation of oral problems in an osteogenesis imperfecta population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:189–196.[ISI][Medline]

Oliveira RJ, Hammer B, Stillman A, Holm J, Jons C, Margolis RH (1992). A look at ear canal changes with jaw motion. Ear Hear 13:464–466.[ISI][Medline]

Pallos D, Hart PS, Cortelli JR, Vian S, Wright JT, Korkko J, et al. (2001). Novel COL1A1 mutation (G559C) [correction of G599C] associated with mild osteogenesis imperfecta and dentinogenesis imperfecta. Arch Oral Biol 46:459–470.[ISI][Medline]

Peterson KJ, Lyons JB, Nowak KS, Takacs CM, Wargo MJ, McPeek MA (2004). Estimating metazoan divergence times with a molecular clock. Proc Natl Acad Sci USA 101:6536–6541.[Abstract/Free Full Text]

Pope FM, Komorowska A, Lee KW, Speight P, Zorawska H, Ranta H, et al. (1992). Ehlers Danlos syndrome type I with novel dental features. J Oral Pathol Med 21:418–421.[ISI][Medline]

Qin C, Brunn JC, Jones J, George A, Ramachandran A, Gorski JP, et al. (2001). A comparative study of sialic acid-rich proteins in rat bone and dentin. Eur J Oral Sci 109:133–141.[ISI][Medline]

Qin C, Baba O, Butler WT (2004). Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Crit Rev Oral Biol Med 15:126–136.[Abstract/Free Full Text]

Qin C, Huang B, Wygant JN, McIntyre BW, McDonald CH, Cook RG, et al. (2006). A chondroitin sulfate chain attached to the bone dentin matrix protein 1 NH2-terminal fragment. J Biol Chem 281:8034–8040.[Abstract/Free Full Text]

Rajpar MH, Koch MJ, Davies RM, Mellody KT, Kielty CM, Dixon MJ (2002). Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization. Hum Mol Genet 11:2559–2565.[Abstract/Free Full Text]

Ranta H, Lukinmaa PL, Knif J (1990). Dentin dysplasia type II: absence of type III collagen in dentin. J Oral Pathol Med 19:160–165.[ISI][Medline]

Ranta H, Lukinmaa PL, Waltimo J (1993). Heritable dentin defects: nosology, pathology, and treatment. Am J Med Genet 45:193–200.[ISI][Medline]

Rauch F, Glorieux FH (2004). Osteogenesis imperfecta. Lancet 363:1377–1385.[ISI][Medline]

Rich A, Crick FH (1955). The structure of collagen. Nature 176:915–916.[Medline]

Ritchie HH, Wang LH (1996). Sequence determination of an extremely acidic rat dentin phosphoprotein. J Biol Chem 271:21695–21698.[Abstract/Free Full Text]

Ritchie HH, Hou H, Veis A, Butler WT (1994). Cloning and sequence determination of rat dentin sialoprotein, a novel dentin protein. J Biol Chem 269:3698–3702.