Hereditary Dentin Defects

INTRODUCTION

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 DEVELOPMENTIn 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

ABSTRACTBy the Shields classification, articulated over 30 years ago,inherited dentin defects are divided into 5 types: 3 types ofdentinogenesis imperfecta (DGI), and 2 types of dentindysplasia (DD). DGI type I is osteogenesis imperfecta (OI)with DGI. OI with DGI is caused, in most cases, bymutations in the 2 genes encoding type I collagen. Manygenes are required to generate the enzymes that catalyzecollagen's diverse post-translational modifications and itsassembly into fibers, fibrils, bundles, and networks. Rareinherited diseases of bone are caused by defects in thesegenes, and some are occasionally found to include DGI as afeature. Appreciation of the complicated genetic etiology ofDGI associated with bony defects splintered the DGI type Idescription into a multitude of more precisely definedentities, all with their own designations. In contrast, DD-II,DGI-II, and DGI-III, each with its own pattern of inheriteddefects limited to the dentition, have been found to becaused by various defects in DSPP (dentin sialophospho -protein), a gene encoding the major non-collagenousproteins of dentin. Only DD-I, an exceedingly rarecondition featuring short, blunt roots with obliterated pulpchambers, remains untouched by the revolution in genetics,and its etiology is still a mystery. A major surprise in thecharacterization of genes underlying inherited dentin defectsis the apparent lack of roles played by the genes encodingthe less-abundant non-collagenous proteins in dentin, suchas dentin matrix protein 1 (DMP1), integrin-bindingsialoprotein (IBSP), matrix extracellular phosphoglyco -protein (MEPE), and secreted phosphoprotein-1, orosteopontin (SPP1, OPN). This review discusses thedevelopment of the dentin extracellular matrix in the contextof its evolution, and discusses the phenotypes and clinicalclassifications of isolated hereditary defects of tooth dentinin the context of recent genetic data respecting their geneticetiologies.

KEY WORDS: dentin, dentin sialophosphoprotein,osteogenesis imperfecta, dentinogenesis imperfecta, dentindysplasia.

Received June 2, 2006; Accepted October 19, 2006

A supplemental appendix to this article is published electronically

only at http://www.dentalresearch.org.

Hereditary Dentin DefectsJ.-W. Kim1 and J.P. Simmer2*1Seoul National University, School of Dentistry Department ofPediatric Dentistry & Dental Research Institute, 28-2 Yongon-dong,Chongno-gu, Seoul, Korea 110-749; and 2Department of Biologic andMaterials Science, University of Michigan School of Dentistry,Dental Research Lab, 1210 Eisenhower Place, Ann Arbor, MI 48108,USA; *corresponding author, [email protected]

J Dent Res 86(5):392-399, 2007

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J Dent Res 86(5) 2007 Hereditary Dentin Defects 393

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).

CLASSIFICATION OF INHERITED DENTIN DEFECTSHereditary conditions affecting dentin have long been evident in

human populations (Gray, 1970). "Hereditary opalescent dentin"

was first proposed to describe inherited dentin defects that

occurred in the absence of systemic, non-dental, manifestations

(Hodge et al., 1936). "Dentinogenesis imperfecta" was used to

describe the dental phenotypes associated with osteogenesis

imperfecta (OI) (Roberts and Schour, 1939). The classification

system currently in use was designed to discriminate among

various patterns of dentin defects and to specifically include a

designation for a mild dentin phenotype classified as dentin

dysplasia type II (Shields et al., 1973). This system recognizes 3

types of dentinogenesis imperfecta [DGI-I (MIM 166240), DGI-II

(MIM #125490), and DGI-III (MIM #125500)] and 2 types of

dentin dysplasia [DD-I (MIM %125400) and DD-II (MIM

#125420)]. When this classification system was conceived, it was

appreciated that, as the genetic causes of inherited dentin defects

became known, revising the nomenclature for hereditary dentin

defects would be necessary (Bixler, 1976). We are now in an

uncomfortable transition period where the current system is

increasingly at odds with genetic findings, but knowledge of the

genes associated with inherited dentin defects has not yet advanced

to a point where a comprehensive etiology-based classification

system can be proposed (Bixler, 1976; Dean et al., 1997). The

dental phenotypes of the 5 divisions of Shields' classification

system are briefly summarized, followed by a more in-depth

review of each division and what has been learned of its etiology.

SUMMARY OF THE SHIELDS CLASSIFICATION

DGI-IThis 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-IIThis 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-IIIThis was first found in the Brandywine tri-racial isolate from

Figure 1. SIBLING genes on human chromosome 4. Key: Dentinsialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1), integrin-binding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein(MEPE), secreted phosphoprotein-1 (SPP1).

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394 Kim & Simmer J Dent Res 86(5) 2007

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-IThe 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-IIThe 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 notobserved. 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).

DENTINOGENESIS IMPERFECTA TYPE I (DGI-I)DGI-I is the dental phenotype associated with OI. OI is a

genetic disorder featuring increased bone fragility, low bone

mass, and other connective tissue manifestations usually caused

by defects in the 2 genes encoding type I collagen (COL1A1,

17q21.31-q22; COL1A2, 7q22.1). The type I collagen triple

helix is a fibril comprised of two alpha 1 chains and one alpha

2 chain. It is the most abundant protein in bone, skin, and other

connective tissues. Because many enzymes are involved in

catalyzing collagen post-translational modifications (3

hydroxylases, 2 glycosyltransferases, 2 proteinases, 2

isomerases, and an oxidase), and many proteins function

through interactions with collagen, defects in many genes can

cause conditions resembling OI, and specific type I collagen

defects can cause diseases other than OI (Myllyharju and

Kivirikko, 2004).

OI is generally classified into 4 clinical types, although 3

Figure 2. Isolated inherited dentin defects. Primary dentition of a personwith DGI-II (top). Bitewing radiographs show pulp obliteration in themolars. Primary dentition of a person with DGI-III (middle). Radiographshows widened pulp and root canals. Several teeth have abscessesfollowing pulp exposure due to rapid attrition. Permanent dentition of aperson with DD-II (bottom). Note the near-normal color of the teeth. Thepulp chambers are smaller than normal (becoming obliteratedprematurely).





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 etal., 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 OIThe 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)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 etal., 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.

No bony defects have been reported in the kindreds with

defined DSPP mutations, even though DSPP is expressed in

both dentin and bone. Potential reasons for the absence of bony

defects include the lower expression of DSPP in bone, tissue-

specific differences in its proteolytic processing (Qin et al.,2001, 2004), and molecular redundancy (the potential for other

bone extracellular matrix molecules to serve the same function

as DSPP). It is also possible that bony phenotypes in DSPPmutation kindreds are subtle and go undetected. In some DGI-

II kindreds with DSPP mutations (p.P17T and p.V18F), older

affected members develop progressive sensorineural high-

frequency hearing loss (DFNA39). Is DSPP expression

especially important in the small bones of the inner ear?

Defects in these bones would be expected to cause conductive,

rather than neurosensory, hearing loss. Progressive hearing loss

is one of the principal symptoms of OI, affecting about 50% of

adult patients (Kuurila et al., 2000). The hearing loss in OI is

predominantly of the conductive type. Progressive hearing loss

in persons with DGI-II might be a secondary effect. Many

persons with DGI-II experience significant dental attrition and

a concomitant loss of vertical dimension (overclosure of the

jaw). Jaw position affects the shape of the inner ear (Oliveira et

al., 1992), and tooth loss, even in

the absence of DGI, can lead to

hearing deficits (Lawrence et al.,2001; Nagasaka et al., 2002).

DENTINOGENESISIMPERFECTA TYPE III (DGI-III)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 DSPPmutation (c.52G→T, p.V18F)

manifested as DGI-II and DGI-

III in different families (Kim etal. , 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)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 DSPPgene, 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)A mutation in the DSPP signal peptide codon (c.16T→G,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 dentinmatrix, but the secreted protein was entirely normal. Sincesome of the mutations underlying DGI-II resulted in no DSPPexpression from the mutant allele (a 50% reduction), thegenetic data were consistent with the interpretation that theDD-II and DGI-II phenotypes are mild and severe forms of thesame disease.

Table. DSPP Mutations Associated with Isolated Inherited Dentin Defects

Location Protein cDNA Gene Diagnosis References

Exon 2 p.Y6D c.16T>G g.16T>G DD-II Rajpar et al., 2002p.A15V c.44C>T g.44C>T DGI-II Malmgren et al., 2004p.P17T c.49C>A g.49C>A DGI-II Xiao et al., 2001

Intron 2 g.1188C>G, IVS23C>G DGI-II Kim et al., 2004Exon 3 p.V18F* c.52G>T g.1191G>T DGI-II Xiao et al., 2001

DGI-III Kim et al., 2005p.Q45X c.133C>T g.1272C>T DGI-II Zhang et al., 2001

Intron 3 g.1275G>A, IVS3+1G>A DGI-II Xiao et al., 2001Exon 4 p.R68W c.202A>T g.1474A>T DGI-II Malmgren et al., 2004Exon 5 Compound (p.1160_1171del & 1198_1199in) DGI-III Dong et al., 2005

* The abbreviations—for example, in row 5—mean that, in the mutant DSPP protein, the valine at aminoacid 18 is changed to phenylalanine (p.V18F); and the guanine at nucleotide 52 in the cDNA (c.52G>T),which is at nucleotide 1191 in exon 3 of the DSPP gene, g.1191G>T, is changed to a thymine.

Figure 3. Human DSPP gene structure and known disease-causing mutations. The boxes are exons, andthe lines are introns. The lines above the gene diagram mark the positions of known disease-causingmutations in DSPP, which are: p.Y6D, p.A15D, p.P17T, Splice IVS2-3C>G, p.V18F, p.Q45X, SpliceIVS3+1G>A, p.R68W, and p.del:1160-1171/p.Ins1198-1199. The amino acids corresponding to theporcine DSPP domain structure (Signal peptide-DSP-DGP-DPP) are shown in parentheses. Much of thehuman DPP coding region in exon 5 is highly redundant and cannot be screened for mutations.





DISCUSSIONIn 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.

ACKNOWLEDGMENTSThis 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.

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