CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

Hereditary Dentin Defects

J.-W. Kim1 and J.P. Simmer2*

INTRODUCTION

1 Seoul

entin is the mineralized tissue constituting the body of a tooth,

D
serving as a protective covering for the pulp and as a support for
overlying enamel and cementum. On a weight basis, mature dentin

National University, School of Dentistry Department of

Pediatric Dentistry & Dental Research Institute, 28-2 Yongon-dong,
Chongno-gu, Seoul, Korea 110-749; and 2Department 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@umich.edu

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

ABSTRACT
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.

Received June 2, 2006; Accepted October 19, 2006

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

392

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

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 singlecelled 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

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J Dent Res 86(5) 2007

Hereditary Dentin Defects

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).

393

Figure 1. SIBLING genes on human chromosome 4. Key: Dentin

sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1), integrinbinding sialoprotein (IBSP), matrix extracellular phosphoglycoprotein
(MEPE), secreted phosphoprotein-1 (SPP1).

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-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.

CLASSIFICATION OF INHERITED DENTIN DEFECTS

DGI-II

Hereditary 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

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

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Kim & Simmer

J Dent Res 86(5) 2007

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 thistletube 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; ClergeauGuerithault 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)

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).

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,

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

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J Dent Res 86(5) 2007

Hereditary Dentin Defects

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

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

395

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 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

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396

Table. DSPP Mutations Associated with Isolated Inherited Dentin Defects

Location

Protein

cDNA

Gene

Diagnosis

Exon 2

p.Y6D
p.A15V
p.P17T

c.16T>G
c.44C>T
c.49C>A

p.V18F*

c.52G>T

g.16T>G
g.44C>T
g.49C>A
g.1188C>G, IVS23C>G
g.1191G>T

DD-II
DGI-II
DGI-II
DGI-II
DGI-II
DGI-III
DGI-II
DGI-II
DGI-II
DGI-III

Intron 2
Exon 3

J Dent Res 86(5) 2007

Kim & Simmer

References
Rajpar et al., 2002
Malmgren et al., 2004
Xiao et al., 2001
Kim et al., 2004
Xiao et al., 2001
Kim et al., 2005
Zhang et al., 2001
Xiao et al., 2001
Malmgren et al., 2004
Dong et al., 2005

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

the absence of DGI, can lead to
hearing deficits (Lawrence et al.,
2001; Nagasaka et al., 2002).

DENTINOGENESIS
IMPERFECTA TYPE III
(DGI-III)

The 2 main features (multiple

pulp exposures and shell teeth)
p.Q45X
c.133C>T
g.1272C>T
used to distinguish DGI-III from
Intron 3
g.1275G>A, IVS3+1G>A
DGI-II are not unique to DGI-III.
Exon 4
p.R68W
c.202A>T
g.1474A>T
The pulp chambers in DGI-II are
Exon 5
Compound (p.1160_1171del & 1198_1199in)
sometimes abnormally wide
initially (shell teeth), but they
* The abbreviationsfor example, in row 5mean that, in the mutant DSPP protein, the valine at amino
progressively obliterate (Heimler
acid 18 is changed to phenylalanine (p.V18F); and the guanine at nucleotide 52 in the cDNA (c.52G>T),
et al., 1985; Ranta et al., 1993;
which is at nucleotide 1191 in exon 3 of the DSPP gene, g.1191G>T, is changed to a thymine.
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 DGIIII in different families (Kim et
Figure 3. Human DSPP gene structure and known disease-causing mutations. The boxes are exons, and
al., 2005), and the genetic
the lines are introns. The lines above the gene diagram mark the positions of known disease-causing
defects underlying the original
mutations in DSPP, which are: p.Y6D, p.A15D, p.P17T, Splice IVS2-3C>G, p.V18F, p.Q45X, Splice
Brandywine phenotype are in
IVS3+1G>A, p.R68W, and p.del:1160-1171/p.Ins1198-1199. The amino acids corresponding to the
DSPP (Dong et al., 2005). 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.
Dspp -/- mouse teeth displayed
relatively severe deficiencies in
root dentin formation, similar to
those in the human DGI-III
known disease-causing mutations is provided in Fig. 3.
phenotype (Sreenath et al., 2003).
No bony defects have been reported in the kindreds with
DENTIN DYSPLASIA TYPE I (DD-I)
defined DSPP mutations, even though DSPP is expressed in
both dentin and bone. Potential reasons for the absence of bony
DD-I is a rare anomaly of unknown etiology that affects
defects include the lower expression of DSPP in bone, tissueapproximately one patient in every 100,000. Several DD-I
specific differences in its proteolytic processing (Qin et al.,
kindreds showed an autosomal-dominant mode of inheritance.
2001, 2004), and molecular redundancy (the potential for other
It is not known if DD-I is another allelic disorder of the DSPP
bone extracellular matrix molecules to serve the same function
gene, or a mixed phenotype. DD-I, DD-II, and DGI-II have
as DSPP). It is also possible that bony phenotypes in DSPP
been observed within a single family (Graham et al., 1965) or
single affected individual (Ciola et al., 1978; Tidwell and
mutation kindreds are subtle and go undetected. In some DGICummingham, 1979; Diamond, 1989).
II kindreds with DSPP mutations (p.P17T and p.V18F), older
affected members develop progressive sensorineural highfrequency hearing loss (DFNA39). Is DSPP expression
DENTIN DYSPLASIA TYPE II (DD-II)
especially important in the small bones of the inner ear?
A mutation in the DSPP signal peptide codon (c.16TG,
Defects in these bones would be expected to cause conductive,
p.Y6D) was identified in a DD-II family (Rajpar et al., 2002).
rather than neurosensory, hearing loss. Progressive hearing loss
The effect of the mutation was a reduction (by less than 50%)
is one of the principal symptoms of OI, affecting about 50% of
of the amount of DSPP secreted into the forming dentin
adult patients (Kuurila et al., 2000). The hearing loss in OI is
matrix, but the secreted protein was entirely normal. Since
predominantly of the conductive type. Progressive hearing loss
some of the mutations underlying DGI-II resulted in no DSPP
in persons with DGI-II might be a secondary effect. Many
expression from the mutant allele (a 50% reduction), the
persons with DGI-II experience significant dental attrition and
genetic data were consistent with the interpretation that the
a concomitant loss of vertical dimension (overclosure of the
DD-II and DGI-II phenotypes are mild and severe forms of the
jaw). Jaw position affects the shape of the inner ear (Oliveira et
same disease.
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Hereditary Dentin Defects

DISCUSSION
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 DSPPderived 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?

397

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.

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