journal of dentistry 40 (2012) 542–548

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Review

Hereditary dentine diseases resulting from mutations

in DSPP gene§
Izabela Maciejewska *, Ewa Chomik
Department of Dental Prosthodontics, Medical University of Gdansk, 18 E. Orzeszkowej St., 80-208 Gdansk, Poland

article info abstract

Article history: Objectives: This review groups the newest results of molecular analyses of DSPP gene for
Received 6 September 2011 patients diagnosed either with dentinogenesis imperfecta type II/III or dentine dysplasia and
Received in revised form tries to link the phenotypes with specific mutations in the DSPP gene.
4 April 2012 Data: The review includes biochemical data introducing a specificity of DSPP protein which
Accepted 5 April 2012 justifies it as a critical factor for dentine mineralization and maturation. The majority of the
review analyzes mutations in the DSPP gene which result in phenotypes of dentinogenesis
imperfecta types II or/and III or dentine dysplasia.
Keywords: Sources: An electronic search was conducted in the databases of Pub Med and supplemented
DSPP by manual study of relevant references.
Dentinogenesis imperfecta type II/III Study selection: 52 out of 108 references were finally selected for the review based on the
Dentine dysplasia novelty and/or originality of data.
Conclusion: Hereditary dentine disorders dentinogenesis imperfecta type II/III and dentine
dysplasia are currently proposed to be one disease with distinct clinical manifestations
reflecting various mutations in the same DSPP gene. For years both disorders were linked
exclusively to mutations in the DSP code but a growing number of papers describe mutations
which manifest a similar phenotype but are localized in the strongly repetitive sequence of
the 30 terminus of the DSPP which codes DPP protein. Our search suggests that the
localization of mutation in the sequence of the DSPP gene might result in a different
phenotype due to the diverse cellular fate of the mutated protein. Thus comprehensive
research on the cellular fate and processing of both normal and mutated DSPP is still
required.
# 2012 Elsevier Ltd. All rights reserved.

effects on tissue function. Mineral represents up to 70% of the

1. Introduction
Dentinogenesis is a strictly controlled process in which an
extra cellular matrix (ECM) is secreted and subsequently
mineralized. These events are under close cellular control by
the formative cells, odontoblasts, and any defect of these cells
can lead to aberrations of dentine formation with consequent
mature dentine while the organic phase accounts for 20% and
is primarily composed of type I collagen.1,2 About 10% of the
organic phase of dentine is composed of various non-
collagenous proteins with DPP, DSP and DGP (dentine
phosphoprotein, dentine sialoprotein, dentine glycoprotein,
respectively) being characteristic components of dentine.
These three ECM molecules originate from a native chimeric

§
Supported by grant: N N403 130040 to IM.
* Corresponding author. Tel.: +48 58 349 2159; fax: +48 58 349 2150.
E-mail address: izabelam@gumed.edu.pl (I. Maciejewska).
0300-5712/$ – see front matter # 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jdent.2012.04.004
 journal of dentistry 40 (2012) 542–548
protein – DSPP (dentine sialophosphoprotein), which is not
found extracellularly due to intracellular post-translational
processing. In humans, DSPP consists of about 1300 amino
acids (aa) and is predominantly expressed in teeth (dentine),
although its presence in bone and several soft tissues has
been detected at much lower3 concentrations. Immediately
after the translation of full-length DSPP, proteases from the
astacin family cleave DSPP into 3 separate daughter proteins
of different properties.4 DSP originates from the N-terminus
of DSPP (aa16-374) and is both N- and O-linked glycosylated
exclusively with chondroitin 6-sulphate glycan5 in rat and
mostly with chondroitin 4-sulphate glycan in bovine.6 The
scrutinized analysis of the spatial conformation of DSP
showed many differences between species.6–8 Similarly, the
differences in the molecular weight of DSP have been
reported.9,10 These discrepancies possibly result from the
fact that in the ECM of dentine, DSP coexists in two forms:
the core protein called DSP and the proteoglycan form called
DSP-PG or DPG.6,7,10 Additionally, DSP might form the
covalently linked dimmers, which were reported in the
cases of both pig and bovine.6,7 DSP’s role in dentine
mineralization has not been elucidated yet. However, it is
believed that it mediates a very early phase of mineral
formation.11,12 Also, the existence of the proteoglycan form
of DSP exposed involvement of GAG chains in the process of
the transition of predentine into dentine.13 The proteogly-
can form of the porcine DGP spans amino acids 375–462, has
4 phosphorylated serine residues and 1 glycosylated
asparagine.14 The N-terminus of DPP begins with an
AspAspProAsn sequence and extends to the C-terminus
for an average 500 aa (in pigs).5,15 The length of the DPP
differs between individuals and is believed to represent a
polymorphism,16 although this does not appear to affect the
DPP’s putative function.17 Due to the large number of Asp,
Glu and Ser residues, DPP is highly hydrophilic and one of
the body’s most acidic proteins. After post-translational
phosphorylation of the Ser residues, mainly localized at the
30 terminus of the DPP, this protein contains an average of
200 phosphates per molecule, which are gathered in the
repeating sequences of Asp-Pse-Pse. The analytical study of
the spatial conformation of these repeats showed that they
produce a ribbon-like, trans-extended chain structure, with
the repetitive arrays of the phosphate and carboxylate
groups, on both edges of the polypeptide chain.18 This
specific spatial arrangement works efficiently for calcium
binding and bridging. Thus the strongly anionic nature and
spatial conformation of the DPP has contributed to its
implication in crystal nucleation and mineral formation.19,20
Nascent and posttranslationally modified DPP migrates
immediately to the mineralization front following secretion,
where it is incorporated into the framework of the
collagenous fibrils and stimulates mineral formation.21
However, the in vitro studies showed that DPP’s role in
dentine mineralization is concentration dependent.22,23
Thus DPP stimulates mineralization at low concentration
whereas it inhibits it at high concentration.22,23 This
inhibitory function of DPP can possibly protect dentine
against being over mineralized.
Molecular analysis of the human genome has localized the
DSPP gene to chromosome 4q22.1. DSPP consists of 5 exons
543
and 4 introns, spanning a total of 8343 base pairs.19 The first
exon is non-coding whereas the second codes mainly the
sequence of a signal peptide. The DSP sequence is coded by the
third and fourth exons and the very short 50 region of exon five.
The entire sequence of DPP is coded on exon five.24,25 The
sequence of human DPP is highly repetitive and contains an
average of 200 tandem copies of 9-bp that encode Ser-Ser-Asp
repeats.26 Moreover, recent data has shown that the C-
terminus of human DPP sequence displays an allelic polymor-
phism, which results in variability in the number of Ser-Ser-
Asp repeats in healthy individuals.26,27
The aim of this paper is to assemble the newest results of
molecular analyses of the DSPP gene for patients diagnosed
either with dentinogenesis imperfecta type II/III or dentine
dysplasia and try to link the phenotypes with specific
mutations in the DSPP gene.
2. Materials and methods
2.1. Data
This review was written to evaluate the most significant and
recent data which emphasize the molecular analysis of
mutations in the DSPP gene resulting in phenotypes of
dentinogenesis imperfecta type II/III (DGI-II/III) or dentine
dysplasia (DD). Only the mutations which result in the
phenotype of dentinogenesis imperfecta type II/III or dentine
dysplasia were described in the manuscript. In the authors
opinion it is critical to query why the same mutation in the
DSPP gene results in the phenotype of dentinogenesis imperfecta
type II in some individuals, whereas others suffer from
dentine dysplasia. Answers to this query can significantly
extend our understanding of whether and how a genetic
background modifies the final phenotype. The authors took up
the challenge of finding correlations (if any) between both the
type and localization of the mutation and the specific
symptoms presented in clinical evaluation.
2.2. Sources
An electronic search of Pub Med databases (up to November
2011) included the following subjects in various combinations:
#1 DSPP; #2 human; #3 teeth; tooth; dental; #4 dentine; #5
dentinogenesis imperfecta type II/III; #6 dentine dysplasia; #7
hereditary disorders; #8 mice; #9 English
The database was searched to include only manuscripts in
English. Polish literature was examined manually.
2.3. Selection criteria
Since both dentinogenesis imperfecta type II/III and dentine
dysplasia are very rare hereditary dentine disorders, our
preliminary search involved 108 relevant references. The
inclusion criteria were manuscripts that evaluated:
1. Composition, formation and structure of dentine.
2. Biochemical data introducing a specificity of DSPP protein.
3. The phenotype of dentinogenesis imperfecta type II/III (DGI-II/
III) and dentine dysplasia (DD).
544 journal of dentistry 40 (2012) 542–548

Electronic search of PubMed

database utilizing keywords
Manual search of
Polish references
(total 108 manuscripts)

56 manuscripts excluded based on

the exclusion criteria

Biochemical data The molecular analysis of

Composition, formation, The phenotype
introducing a specificity mutations within DSPP gene
and structure of dentine of DSPP protein of DGI-II/III and DD. resulting in phenotypes of
DGI-II/III and DD

Screening of titles and abstracts

(52 manuscripts selected
and accepted)

Fig. 1 – Selection criteria for the chosen references.

4. The molecular analysis of mutations within the DSPP gene
resulting in phenotypes of DGI-II/III and DD.
Under the criteria of novelty and originality, data presented
in 52 of them was classified for further evaluation.
Letters to the editor, historical reviews, abstracts, posters,
chapters in textbooks and unpublished articles were not
sought (Fig. 1).
3. Results and discussion
To date, solely mutations in DSPP have been linked to the
isolated hereditary disorders of dentine formation, which
were originally categorized as dentinogenesis imperfecta and
dentine dysplasia.28 Dentinogenesis imperfecta type II (OMIM
125490), also called opalescent dentine, is reported to have an
incidence ranging from 1 in 6000 to 1 in 8000 of live births29;
however, the epidemiological data is very limited. Commonly
described clinical symptoms include yellow, amber brown or
bluish grey discolouration and substantial translucency of the
teeth. Histologically, the dentine of these teeth shows a
limited number or complete lack of dentine tubules with
significantly reduced and defective dentine mineralization.
Due to the softness of the underlying dentine, enamel tends to
chip off leading to the rapidly progressive attrition of the teeth.
Radiologically, teeth show bulbous crowns with cervical
constrictions at the root junction. Roots are smaller and
narrower compared to healthy teeth. Pulp chambers and root
canals are usually obliterated.12,30 The same features clinically
diagnosed in the deciduous teeth are classified as dentine
dysplasia type II (DD-II)(OMIM 125420). The permanent teeth in
patients with dentine dysplasia type II are much less affected;
however, radiologically these teeth show thistle-tube pulp
chambers with multiple pulp stones.12,16,31
To date, the incidence of dentinogenesis imperfecta type III
(OMIM 125500) has been associated with descendents of an
isolated tri-racial sub-population known as the ‘‘Brandywine
isolate’’. This population was originally located in Southern
Maryland, USA (in the Brandywine river valley) and the
incidence of DGI-III has been estimated at 1 in 15 live births in
that population.12 Despite close clinical similarities to DGI-II, a
significant difference is seen radiographically with the
presence of so-called ‘‘shell teeth’’ with enlarged, poorly
mineralized pulp chambers and widened root canals.32,33 An
animal study confirmed that DSPP knock-out mice show a
phenotype that resembles human dentinogenesis imperfecta
type III.34
It is important to emphasize that the initial classification of
dentinogenesis imperfecta and dentine dysplasia has been based
on the clinical and radiologic symptoms without substantial
knowledge of the molecular pathogenesis. Thus the challenge
of current research is to establish the correlation between
particular genetic mutations in the sequence of the DSPP gene
and related clinical features manifested in the phenotype. To
date, more than 30 mutations in the DSPP gene have been
reported,17,35,36 although some of them do not result in the
phenotype of dentinogenesis imperfecta type II or dentine
dysplasia. Due to ‘‘degeneracy’’ of codons, the mutational
change of the third nucleotide in a codon (except ATG and
TGG) often remains silent. The same relates to the insertion
and/or deletion of three consequent nucleotides (entire codon/
s) which does not cause a frameshift.17
According to the DSPP sequence, mutations have been
arbitrarily divided into 3 groups; those that appear in the
coding sequence of: (1) the signal peptide, (2) DSP or (3) DPP. It is
interesting that in the coding sequences of the signal peptide
and/or DSP code, there have been detected mostly the
nonsense and/or missense mutations, while the phenotype
related mutations that appear in the DPP coding sequence are
generally deletions or insertions resulting in a frameshift.
Mutations in the sequence of the signal peptide of DSPP
have been described in two papers20,37 and both were of a
missensenature (Table 1). The first one was reported in codon
6 (T>G) and resulted in the substitution of the hydrophobic Tyr
for the hydrophilic Asp at the 6th codon of the hydrophobic
 journal of dentistry 40 (2012) 542–548 545

Table 1 – Mutations within the signal peptide of DSPP.

Races Mutation cDNA Amino Predicted Sequences Exon Diagnosis References
class acid protein
20
Caucasian/German Missense c.16T>G Pro17Thr p.Y6D TAT>GAT 2 DD-II
37
Central American Missense c.15C>T Ala15Val p.A15V GCC>GTC 2 DGI-II

core of the signal peptide domain.20 This mutation reflected
the phenotype of dentine dysplasia II presented by all affected
members of the family. In contrast, the transition of C>T in the
last 15th codon of the DSPP signal peptide caused the
substitution of Ala with Val and resulted in the clinically
diagnosed dentinogenesis imperfecta type II.37 It has been
proposed that the mutations in the signal peptide of DSPP
lead to impaired or no translocation of the protein into the
endoplasmic reticulum (ER).20 Subsequently, the protein does
not undergo the usual intense post-translational modifica-
tions and is degraded in the cellular cytosol or becomes
immobilized in the membrane of the ER, reducing its
availability and function. Consequently, this reduces the
amount of both DSP and DPP secreted into the extracellular
matrix, which impacts on the entire process of dentine
deposition and mineralization. A similar explanation for the
severe phenotype of dentinogenesis imperfecta type II or III in
members of a few families has also been proposed32,35,36,38–41
(Table 2). The authors described the transversion of c.49 (C>A
or C>T) which resulted in the substitution of p.17 Pro into
Thror Ser, respectively39,41,42 as well as the transversion of c.52
(G>T) that caused the substitution of p.18Val into Phe.38,39,43,44
Since the C-terminus of the signal peptide and the first 3
amino acids (especially Pro at the 2nd and Val at 3rd positions,
respectively) of the mature protein contain the signal
peptidase cleavage site, it is conceivable that a missense
mutation in the first three amino acids of the mature DSPP
leads to errors in signal peptide processing; however, such
correlations between specific point mutations and the
observed phenotype still have to be demonstrated.
DSPP mutations that appear in the DSP code and those that
appear in the first three amino acids usually manifest a
phenotype of dentinogenesis imperfecta type II37–39,43,45 (Table 2).
Generally, discolouration of both deciduous and permanent
teeth is observed with accompanying cuspal attrition and pulp
chamber obliteration.47 In the 50 sequence of DSPP that
encodes DSP, a transition was detected particularly in the
c.133 (C>T)38,47 of exon 3 and resulted in the nonsense p.Gln 45
stop mutation. The nonsense mutations are responsible for
the premature termination of transcription that conceivably
results in incomplete translation and truncated DSPP forma-
tion; thus only DSP is formed. The phenotype which resulted
from the nonsense mutation c.133 (C>T) observed in Song’s
study38 revealed the deposition of abnormal dentine with a

Table 2 – Mutations in the coding sequence of DSP, including changes within the conserved Ile–Pro–Val domain and exon
3 skipping.
Races Mutation class cDNA Amino Predicted Sequences Exon/ Diagnosis References
acid protein intron
41,42
Brandywine Missense c.49C>T Pro17Ser p.P17S CCA>TCA Exon 2 DGI-II
triracial
isolate/Chinese
39
Chinese Missense c.49C>A Pro17Thr p.P17T CCA>ACA Exon 2 DGI-II with
hearing loss
39
Chinese Missense c.52G>T Val18Phe p.V18F GTT>TTT Exon 3 DGI-II with
hearing loss
43
Caucasian Missense c.52G>T Val18Phe p. V18F GTT>TTT Exon 3 DGI-II
44
Finnish Missense g.1197G>T Val18Phe p.V18F GTT>TTT Exon 3 DGI-II
38,43
Korean/ Missense c.52G>T Val18Phe p.V18F GTT>TTT Exon 3 DGI-III
Chinese
36,40
Korean Missense c.53T>A Val18Asp p.V18D GTC>GAC Exon 3 DGI-II
g.1198T>A
35
Japanese Missense c.53T>A Val18Asp p.V18D GTC>GAC Exon 3 DGI-II
g.1192T>A
38
Chinese Nonsense c.133C>T Gln45 STOP p.Q45X CAG>TAG Exon 3 DGI-II
47
Chinese Nonsense c.3658C>T Gln45 STOP p.Q45X CAG>TAG Exon 3 DGI-II
37
Sweden Missense c.68A>T Arg68Trp p.R68W AGG>TGG Exon 4 DGI-II
44
Caucasian Missense c.202A>T Arg68Trp p.R68W AGG>TGG Exon 4 DGI-II
48
Korean Splicing site mutation g.1188C>G, – p.V18_Q45del CAG>GAG Intron 2 DGI-II
IVS23C>G
44
Caucasian/ Splicing site mutation g.1194C>A – p.V18_Q45del CAG>AAG Intron 2 DGI-II
Finnish
46
Mongolian Splicing site mutation IVS3+3A>G – – GTAT>GTGT Intron 3 DGI-II
39
Chinese Splicing site mutation, c.135+ – p.V18_Q45del TACAGg/a Intron 3 DGI-II
skipping of exon 3 1 G>A
26
Caucasian Splicing site mutation, c.135+ – p.V18_Q45del TACAGg/t Intron 3 DGI-II
skipping of exon 3 1 G>T
546 journal of dentistry 40 (2012) 542–548

reduced number and orientation of dentinal tubules and the
presence of dense, amorphous masses inside the dentine
tubules. With polymorphism analysis, Xiao et al. described
another mutation occurring in the coding sequence of DSP,
which revealed a G>A transition (c.135) in the donor splice site
of intron 3 possibly resulting in the skipping of the entire exon
3.39 The hypothesis of the skipping of exon 3 was also
discussed by McKnight et al.,26 who described the transversion
of G>T in the codon 135 and DNA sequence analysis led to
their proposal that the mutation is responsible for a loss of
function change in the functional acceptor site at the 50 side of
the exon 4 splicing sequence, with the 50 bp long sequence
void of an alternative strong splice acceptor site. Both those
and others mutations44,46–48 that resulted in the skipping of
the exon 3 manifested the severe phenotype of dentinogenesis
imperfecta type II with progressive attrition and discolouration
of teeth and obliteration of pulp chambers; however, there
were no accompanying reports of progressive hearing
loss.26,39,46 It is difficult to speculate whether the mutations
(but not nonsense mutation) that occur in the DSP sequence of
the DSPP gene result exclusively in the disruption of DSP
formation or if they influence the DPP protein as well.
Research on biomineralization suggests that DSP mediates
early dentine formation and the different pools of proteogly-
cans, isolated from different fractions of dentine (predentine,
dentine-predentine interface, dentine) mediate the transition
of predentine into dentine,13,49 including the timing of
fibrillogenesis along with fibrils alignment and aggregation.
Thus the phenotype resulting from mutations in the DSP
sequence might support the hypothesis that the role of DSP
and/or DSP-PG in dentine formation is irreplaceable and
cannot be balanced by any other protein of the extracellular
matrix of dentine.
Recently, considerable research indicates that the greatest
diversity in phenotypes reflecting disrupted dentine formation
is manifested by mutations that appear in exon 5 of the DSPP
gene which encodes entire DPP26 (Table 3). To date, all
mutations discovered in exon 5 are deletions and/or insertions
with an accompanying frameshift.17,26,32,44,50,51 The first
comprehensive study of the DSPP sequence, which included
the repetitive domain of over 200 tandem copies of 9 bp
repeats, was described by McKnight et al.26,51 The authors
reported five different mutations which resulted in the reading
frameshift that consequently led to a change in the repetitive
sequences of three hydrophilic and phosphorylated aminoa-
cids (Ser-Ser-Asp) into a long sequence that encoded hydro-
phobic amino acids like Val, Ala, Ile. DNA sequencing showed
either one or four nucleotide deletions that were localized in
the 30 terminal region of the DSPP gene (c.1870del TCAG;
c.1918del TCAG; c.2272del A; c.2525del G; c.3141del C,
respectively). The results of McKnight’s study showed that
hundreds of changed amino acids at the 30 terminal fragment
of DPP resulted in the phenotypes of both dentine dysplasia
and/or dentinogenesis imperfecta type II. Surprisingly, the
authors suggested that the longer sequence change (600
codons) resulted in the phenotype of dentine dysplasia,
whereas a change in the shorter hydrophobic sequence
(<500 codons) was manifested by the permanent teeth injury
classified as dentinogenesis imperfecta type II. Although they
carried out detailed studies, the authors were not able to
define why the specific deletion caused the phenotype of
dentine dysplasia whereas others resulted in dentinogenesis
imperfecta type II and speculated that this might be connected
with gene polymorphism and hyplotypes formation. Thus the
final phenotype reflected the activity of a dominant allele,
which might be mutated or not.26,51
The great diversity in haplotypes of the DSPP sequence and
difficulty in sequencing the highly repetitive 30 terminal
fragment of the gene have made it difficult to conduct a full
analysis of exon 5. It is only recently that a growing number of
studies have suggested that the majority of cases of hereditary
dentine disorders might result from mutations causing the
reading frameshift in the 30 terminal fragment of exon 5. A
recent comprehensive study, based on kindred from 12
unrelated families, has linked the specific phenotypes to the
type of mutation.17 It was shown that short span deletions (1–4
nt) which localized closer to the 50 terminal fragment of the
DPP code were manifested by milder tooth discolouration and
smaller changes in pulp chamber anatomy than deletions that
appeared in the most repetitive 30 terminal fragment of DPP.
Additionally, it was shown that the more codons that were
deleted, the more severe the phenotype was. This phenotype
manifested dark discolouration of both dentition, complete
chamber obliteration, and severe teeth attrition, eventually
followed by frequent periapical infections. The Nieminen
et al.’s study clearly demonstrated that only frameshift

Table 3 – Mutations within DPP code.

Races/country Mutation class cDNA Predicted protein Exon Diagnosis References
32
Brandywine Isolate/USA Insertion/deletion c.3599_3634 del 36bp – 5 DGI-III
c.3715_3716 ins 18bp
26
Caucasian Frameshift c.1870delTCAG p.S624TfsX687 5 DD-II
26
Caucasian Frameshift c.1918delTCAG p.S640TfsX671 5 DD-II
17
Greek Frameshift c.1918delTCAG p.S640TfsX671 5 DD-II
26
Caucasian/Northern European Frameshift c.2272delA p.S758AfsX554 5 DGI-II
26
Caucasian/Northern European Frameshift c.2525delG p.S842TfsX471 5 DGI-II
17
Caucasian/Finnish Frameshift c.2063delA – 5 DD-II
17
Caucasian/Finnish Frameshift c.3582del 10bp – 5 DGI-III
50
Korean Frameshift c.2688delT – 5 DGI-II
50
Korean Frameshift c.3560delG – 5 DGI-II
44
Caucasian/Finnish Frameshift g.3599del34bp – 5 DGI-III
44
Caucasian/Finnish Frameshift g.3715ins2bp – 5 DGI-III
51
Not reported Frameshift c.3141delC – 5 DD-II
 journal of dentistry 40 (2012) 542–548
mutations led to the phenotypes of dentinogenesis imperfecta
type II or dentine dysplasia, whereas in frame mutations did
not cause observable clinical changes.17
4. Conclusions
Even though the sophisticated methods used currently for
molecular analysis of the DSPP gene precisely define types
and localizations of DSPP mutations, the direct correlation
between the specific mutation and manifested clinical
symptoms is not possible yet. Possibly, there are many
other contributing factors together with environmental
ones52 which, acting in concert with genetics, influence
the final phenotype observed in the patients diagnosed with
dentinogenesis imperfecta type II or dentine dysplasia. Clinical
diagnosis of dentinogenesis imperfecta type II and dentine
dysplasia includes recognition of a cluster of symptoms that
accompany this hereditary dentine disorder(s), although
individual cases differ one from another in regard to teeth
discolouration, cervical region constriction, presence of
pulp stones, severity of teeth attrition or coexistence of
periapical inflammation. Thus detailed progressive clinical
evaluations of probants and their multi-generation families
seem critical. The histological study of mutated teeth, both
deciduous and permanent, could bring more data as well.
It is not clear yet whether the mutated DSPP molecule is
processed in ER and subsequent organelles prior to final
release into the extracellular matrix of dentine or if a change in
the chemical properties of DSPP results in aggregation of
unprocessed DSPP in the cytosol of odontoblasts. It might be
speculated that the most frequent mutations, which appear in
the code for the signal peptide and/or three first amino acids of
the coding sequence of DSPP, impact on the transport and
processing of the mutated protein, leading to it becoming
trapped and blocking cellular events in the rough ER. This
might eventually affect translation of DSPP and also other
proteins resulting in disrupted dentine formation. However,
the reading frameshift mutations of the DPP code change the
properties of DPP, which may disrupt the entire process of
dentine maturation, eventually resulting in the severe
phenotype of dentinogenesis imperfecta type II and/or dentine
dysplasia. There is thus considerable scope for further
research at the cellular level to determine the mechanistic
effects of DSPP mutations. So far researchers mostly speculate
about the potential protein formation, predicting the final
protein sequence from the analysis of the sequence of
mutated DNA, although the most specific data would come
from the direct co-evaluation of both the mutated gene and
protein. Such a detailed analysis should precisely answer the
query about what ‘‘protein’’ is formed from the specifically
mutated gene.
The use of DSPP gene sequencing, especially for the
repetitive sequence of the DPP code, is important in the
clinical diagnosis of patients with dentinogenesis imperfecta type
II/III and dentine dysplasia, but our understanding of the
cellular fate of mutated DSPP is still unclear. Such knowledge
may help to underpin future molecular therapies for these
patients and thus comprehensive research on the cellular fate
and processing of both normal and mutated DSPP is required.
547
Acknowledgement
The authors acknowledge the helpful advice of Dr. AJ Smith
and Mr. Michael Liley.
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