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INTRODUCTION
1 Seoul
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.
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).
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393
DGI-II
DGI-III
This was first found in the Brandywine tri-racial isolate from
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394
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).
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396
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
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
DENTINOGENESIS
IMPERFECTA TYPE III
(DGI-III)
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
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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