Dentinogenesis imperfecta type II: an affected family saga.

J Oral Sci. 2007 Sep;49(3):241-4

Authors: Kamboj M, Chandra A

Dentinogenesis imperfecta (DI) type II or hereditary opalescent dentin is inherited in simple autosomal dominant mode with high penetrance and low mutation rate. It generally affects both the deciduous and permanent dentitions. DI type II corresponds to a localized form of mesodermal dysplasia, observed in histodifferentiation. Early diagnosis and treatment are therefore, fundamental, aiming at obtaining a favourable prognosis since late intervention makes treatment more complex. We present two cases of DI type II with the disease affecting three generations of a family in India, and briefly highlight the molecular basis of this disease. (J. Oral Sci. 49, 241-244, 2007).

PMID: 17928732 [PubMed - in process]

A novel DSPP mutation is associated with type II dentinogenesis imperfecta in a Chinese family.

BMC Med Genet. 2007;8:52

Authors: Zhang X, Chen L, Liu J, Zhao Z, Qu E, Wang X, Chang W, Xu C, Wang QK, Liu M

BACKGROUND: Hereditary defects of tooth dentin are classified into two main groups: dentin dysplasia (DD) (types I and II) and dentinogenesis imperfecta (DGI) (types I, II, and III). Type II DGI is one of the most common tooth defects with an autosomal dominant mode of inheritance. One disease-causing gene, the dentin sialophosphoprotein (DSPP) gene, has been reported for type II DGI. METHODS: In this study, we characterized a four-generation Chinese family with type II DGI that consists of 18 living family members, including 8 affected individuals. Linkage analysis with polymorphic markers D4S1534 and D4S414 that span the DSPP gene showed that the family is linked to DSPP. All five exons and exon-intron boundaries of DSPP were sequenced in members of type II DGI family. RESULTS: Direct DNA sequence analysis identified a novel mutation (c.49C-->T, p.Pro17Ser) in exon 1 of the DSPP gene. The mutation spot, the Pro17 residue, is the second amino acid of the mature DSP protein, and highly conserved during evolution. The mutation was identified in all affected individuals, but not in normal family members and 100 controls. CONCLUSION: These results suggest that mutation p.Pro17Ser causes type II DGI in the Chinese family. This study identifies a novel mutation in the DSPP gene, and expands the spectrum of mutations that cause DGI.

PMID: 17686168 [PubMed - indexed for MEDLINE]

Increased Young's modulus and hardness of Col1a2oim dentin.

J Dent Res. 2006 Nov;85(11):1032-6

Authors: Lopez Franco GE, Huang A, Pleshko Camacho N, Stone DS, Blank RD

Mice harboring the Col1a2(oim) mutation (oim) express dentinogenesis imperfecta. To determine the effect of Col1a2 genotype on tissue mechanical properties, we compared Young's modulus and hardness of dentin in the 3 Col1a2 genotypes. Upper incisors were tested by nanoindentation. Genotype had a significant effect on Young's modulus, but there was not a simple mutant allele dosage relationship. The effect of genotype on hardness did not reach significance. Hardness and Young's modulus were greater near the dento-enamel junction than near the pulp chamber. Greater hardness and Young's modulus values near the dento-enamel junction reflected continued mineralization of the dentin following its initial synthesis. Analysis showed the mechanical data to be consistent with Fourier transform infrared and backscattered electron microscopy studies that revealed increased mineralization in oim bone. Analysis of the data suggests that clinical fragility of teeth in oim mice is not due to deficiencies of hardness or Young's modulus, but may be due to defects in post-yield behavior or resistance to fatigue damage.

PMID: 17062745 [PubMed - indexed for MEDLINE]

Phenotypic variation in dentinogenesis imperfecta/dentin dysplasia linked to 4q21.

J Dent Res. 2006 Apr;85(4):329-33

Authors: Beattie ML, Kim JW, Gong SG, Murdoch-Kinch CA, Simmer JP, Hu JC

Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders that primarily affect the formation of tooth dentin. Both conditions are autosomal-dominant and can be caused by mutations in the dentin sialophosphoprotein gene (DSPP, 4q21.3). We recruited 23 members of a four-generation kindred, including ten persons with dentin defects, and tested the hypothesis that these defects are linked to DSPP. The primary dentition showed amber discoloration, pulp obliteration, and severe attrition. The secondary dentition showed either pulp obliteration with bulbous crowns and gray discoloration or thistle-tube pulp configurations, normal crowns, and mild gray discoloration. Haplotype analyses showed no recombination between three 4q21-q24 markers and the disease locus. Mutational analyses identified no coding or intron junction sequence variations associated with affection status in DMP1, MEPE, or the DSP portion of DSPP. The defects in the permanent dentition were typically mild and consistent with a diagnosis of DD-II, but some dental features associated with DGI-II were also present. We conclude that DD-II and DGI-II are milder and more severe forms, respectively, of the same disease.

PMID: 16567553 [PubMed - indexed for MEDLINE]

[Clinical, radiographic and laboratory evaluation of patients with osteogenesis imperfecta]

Rev Assoc Med Bras. 2005 Jul-Aug;51(4):214-20

Authors: Santili C, Akkari M, Waisberg G, Bastos Júnior JO, Ferreira WM

BACKGROUND: Osteogenesis imperfecta is a genetic disorder characterized by defects in type I collagen. The main symptom is bone fragility and susceptibility to fractures. Other clinical findings are dentinogenesis imperfecta, blue sclera, early deafness and joint laxity. The purpose of this paper is to establish a practical relationship of the clinical differences between the Sillence's groups. METHODS: 22 patients were classified according to Sillence et al criteria and submitted to laboratory tests including blood calcium level and bone densitometry. RESULTS: All clinical and laboratory differences were discussed in the text. CONCLUSIONS: Differences such as results that were found in walking ability, height and bone densitometry were significant and may help to classify patients and to establish prognosis.

PMID: 16127582 [PubMed - indexed for MEDLINE]

Development of an odontoblast in vitro model to study dentin mineralization.

Connect Tissue Res. 2004;45(2):101-8

Authors: Magne D, Bluteau G, Lopez-Cazaux S, Weiss P, Pilet P, Ritchie HH, Daculsi G, Guicheux J

The aim of the present work was to characterize the odontoblastic proliferation, differentiation, and matrix mineralization in culture of the recently established M2H4 rat cell line. Proliferation was assessed by cell counts, differentiation by RT-PCR analysis, and mineralization by alizarin red staining, atomic absorption spectrometry, and FTIR microspectroscopy. The results showed that M2H4 cell behavior closely mimics in vivo odontoblast differentiation, with, in particular, temporally regulated expression of DMP-1 and DSPP. Moreover, the mineral phase formed by M2H4 cells was similar to that in dentin from rat incisors. Finally, because in mice, transforming growth factor (TGF)-beta1 over-expression in vivo leads to an hypomineralization similar to that observed in dentinogenesis imperfecta type II, effects of TGF-beta1 on mineralization in M2H4 cell culture were studied. Treatment with TGF-beta1 dramatically reduced mineralization, whereas positive control treatment with bone morphogenetic protein-4 enhanced it, suggesting that M2H4 cell line is a promising tool to explore the mineralization mechanisms in physiopathologic conditions.

PMID: 15763925 [PubMed - indexed for MEDLINE]

Amelogenesis imperfecta in a new animal model--a mutation in chromosome 5 (human 4q21).

J Dent Res. 2004 Aug;83(8):608-12

Authors: Seedorf H, Springer IN, Grundner-Culemann E, Albers HK, Reis A, Fuchs H, Hrabe de Angelis M, Açil Y

Candidate genes for amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are located on 4q21 in humans. We tested our hypothesis that mutations in the portion of mouse chromosome 5 corresponding to human chromosome 4q21 would cause enamel and dentin abnormalities. Male C3H mice were injected with ethylnitrosourea (ENU). Within a dominant ENU mutagenesis screen, a mouse mutant was isolated with an abnormal tooth enamel (ATE) phenotype. The structure and ultrastructure of teeth were studied. The mutation was located on mouse chromosome 5 in an interval of 9 cM between markers D5Mit18 and D5Mit10. Homozygotic mutants showed total enamel aplasia with exposed dentinal tubules, while heterozygotic mutants showed a significant reduction in enamel width. Dentin of mutant mice showed a reduced content of mature collagen cross-links. We were able to demonstrate that a mutation on chromosome 5 corresponding to human chromosome 4q21 can cause amelogenesis imperfecta and changes in dentin composition.

PMID: 15271968 [PubMed - indexed for MEDLINE]

Deletion of dentin matrix protein-1 leads to a partial failure of maturation of predentin into dentin, hypomineralization, and expanded cavities of pulp and root canal during postnatal tooth development.

J Biol Chem. 2004 Apr 30;279(18):19141-8

Authors: Ye L, MacDougall M, Zhang S, Xie Y, Zhang J, Li Z, Lu Y, Mishina Y, Feng JQ

The dentin matrix protein-1 (DMP-1) gene is identified in odontoblasts during both embryonic and postnatal development. In vitro study suggests that this noncollagen acidic phosphoprotein plays a role in mineralization. However, deletion of the Dmp-1 gene has little effect on tooth development during embryogenesis. To address the role of DMP-1 in tooth during postnatal development, we analyzed changes of dentinogenesis in Dmp-1 null mice from 3 days after birth to 1 year. Here we show that Dmp-1 null mice postnatally develop a profound tooth phenotype characterized by a partial failure of maturation of predentin into dentin, enlarged pulp chambers, increased width of predentin zone with reduced dentin wall, and hypomineralization. The tooth phenotype of these mice is strikingly similar to that in dentin sialophosphoprotein (Dspp) null mice and shares some features of the human disease dentinogenesis imperfecta III. We have also demonstrated that DSPP levels are reduced in Dmp-1 null mice, suggesting that DSPP is probably regulated by DMP-1 during dentinogenesis. Finally, we show the absence or delayed development of the third molar in Dmp-1 null mice, which is probably secondary to defects in Dmp-1 null bone. Taken together, these studies suggest that DMP-1 is essential for later dentinogenesis during postnatal development.

PMID: 14966118 [PubMed - indexed for MEDLINE]

Laminin alpha2 is essential for odontoblast differentiation regulating dentin sialoprotein expression.

J Biol Chem. 2004 Mar 12;279(11):10286-92

Authors: Yuasa K, Fukumoto S, Kamasaki Y, Yamada A, Fukumoto E, Kanaoka K, Saito K, Harada H, Arikawa-Hirasawa E, Miyagoe-Suzuki Y, Takeda S, Okamoto K, Kato Y, Fujiwara T

Laminin alpha2 is subunit of laminin-2 (alpha2beta1gamma1), which is a major component of the muscle basement membrane. Although the laminin alpha2 chain is expressed in the early stage of dental mesenchyme development and localized in the tooth germ basement membrane, its expression pattern in the late stage of tooth germ development and molecular roles are not clearly understood. We analyzed the role of laminin alpha2 in tooth development by using targeted mice with a disrupted lama2 gene. Laminin alpha2 is expressed in dental mesenchymal cells, especially in odontoblasts and during the maturation stage of ameloblasts, but not in the pre-secretory or secretory stages of ameloblasts. Lama2 mutant mice have thin dentin and a widely opened dentinal tube, as compared with wild-type and heterozygote mice, which is similar to the phenotype of dentinogenesis imperfecta. During dentin formation, the expression of dentin sialoprotein, a marker of odontoblast differentiation, was found to be decreased in odontoblasts from mutant mice. Furthermore, in primary cultures of dental mesenchymal cells, dentin matrix protein, and dentin sialophosphoprotein, mRNA expression was increased in laminin-2 coated dishes but not in those coated with other matrices, fibronectin, or type I collagen. Our results suggest that laminin alpha2 is essential for odontoblast differentiation and regulates the expression of dentin matrix proteins.

PMID: 14681233 [PubMed - indexed for MEDLINE]

Orthodontic and orthognathic management of a patient with osteogenesis imperfecta and dentinogenesis imperfecta: a case report.

J Orthod. 2003 Dec;30(4):291-6

Authors: Kindelan J, Tobin M, Roberts-Harry D, Loukota RA

This case report describes a patient's severe Class III malocclusion, managed with a combination of orthodontic and orthognathic treatment. The medical history was complicated by osteogenesis imperfecta and dentinogenesis imperfecta. In addition the patient was a Jehovah's Witness. Patients with osteogenesis imperfecta carry an increased risk of perioperative haemorrhage, and this led to bimaxillary surgery being carried out as two discrete surgical episodes for the patient described. In addition, the risk of enamel fracture led to orthodontic bands being cemented on all teeth. In spite of the increased risks a successful outcome was achieved.

PMID: 14634166 [PubMed - indexed for MEDLINE]

The importance of intrafibrillar mineralization of collagen on the mechanical properties of dentin.

J Dent Res. 2003 Dec;82(12):957-61

Authors: Kinney JH, Habelitz S, Marshall SJ, Marshall GW

It is widely held that the hardness and modulus of dentin increase in proportion to the mineral concentration. To test this belief, we measured hardness and modulus of normal dentin and an altered form of dentin without gap-zone mineralization in wet and dry conditions by AFM nanoindentation to determine if the modulus and hardness scale linearly with mineral concentration. Mineral concentrations in the mid-coronal location of the normal and altered dentins were 44.4 vol% and 30.9 vol%, respectively. Surrounding the pulp of the altered dentin was a region of higher mineralization, 40.5 vol%. The indentation modulus of normal dentin was 23.9 (SD = 1.1) GPa dry and 20.0 (SD = 1.0) GPa wet. In mid-coronal regions of the altered dentin, the indentation modulus was 13.8 (SD = 2.0) GPa dry and 5.7 (SD = 1.4) GPa wet. In the more mineralized regions of the altered dentin, the modulus was 20.4 (SD = 1.8) GPa dry and 5.3 (SD = 0.8) GPa wet; the properties of the altered wet dentin did not correlate with mineral concentration. The results of this study raise doubt as to whether mineral concentration alone is a sufficient endpoint for assessing the success or failure of remineralization approaches in restorative dentistry.

PMID: 14630894 [PubMed - indexed for MEDLINE]

Dentin sialophosphoprotein knockout mouse teeth display widened predentin zone and develop defective dentin mineralization similar to human dentinogenesis imperfecta type III.

J Biol Chem. 2003 Jul 4;278(27):24874-80

Authors: Sreenath T, Thyagarajan T, Hall B, Longenecker G, D'Souza R, Hong S, Wright JT, MacDougall M, Sauk J, Kulkarni AB

Dentin sialophosphoprotein (Dspp) is mainly expressed in teeth by the odontoblasts and preameloblasts. The Dspp mRNA is translated into a single protein, Dspp, and cleaved into two peptides, dentin sialoprotein and dentin phosphoprotein, that are localized within the dentin matrix. Recently, mutations in this gene were identified in human dentinogenesis imperfecta II (Online Mendelian Inheritance in Man (OMIM) accession number 125490) and in dentin dysplasia II (OMIM accession number 125420) syndromes. Herein, we report the generation of Dspp-null mice that develop tooth defects similar to human dentinogenesis imperfecta III with enlarged pulp chambers, increased width of predentin zone, hypomineralization, and pulp exposure. Electron microscopy revealed an irregular mineralization front and a lack of calcospherites coalescence in the dentin. Interestingly, the levels of biglycan and decorin, small leucine-rich proteoglycans, were increased in the widened predentin zone and in void spaces among the calcospherites in the dentin of null teeth. These enhanced levels correlate well with the defective regions in mineralization and further indicate that these molecules may adversely affect the dentin mineralization process by interfering with coalescence of calcospherites. Overall, our results identify a crucial role for Dspp in orchestrating the events essential during dentin mineralization, including potential regulation of proteoglycan levels.

PMID: 12721295 [PubMed - indexed for MEDLINE]

COL1A1 mutation analysis in Lithuanian patients with osteogenesis imperfecta.

J Appl Genet. 2003;44(1):95-102

Authors: Benusiené E, Kucinskas V

Osteogenesis imperfecta (OI) is a generalised disorder of connective tissue characterised by an increased fragility of bones and also manifested in other tissues containing collagen type I, by blue sclera, hearing loss, dentinogenesis imperfecta, hyperextensible joints, hernias and easy bruising. OI is dominantly inherited and results in >90% OI cases, caused by mutations in one of the two genes COL1A1 or COL1A2 coding for type I procollagen. The Lithuanian OI database comprises 147 case records covering the period of 1980 - 2001. Clinical and genealogical analysis of OI cases/families from Lithuania available for examination revealed 18 familial cases of OI type I and 22 sporadic cases: OI type II (3 cases), OI type III (11 cases) and OI type I (8 cases). As a result of their molecular genetic investigation, 11 mutations were identified in the COL1A1 gene in 13 unrelated patients. Of them, nine mutations (E500X, G481A, c.2046insCTCTCTAG, c.1668delT, c.1667insC, c.4337insC, IVS19+1G > A, IVS20-2A > G, IVS22-1G > T) appeared to be novel, i.e. not yet registered in the Human Type I and Type III Collagen Mutations Database (http://www.le.ac.uk/genetics/collagen).

PMID: 12590186 [PubMed - indexed for MEDLINE]

Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization.

Hum Mol Genet. 2002 Oct 1;11(21):2559-65

Authors: Rajpar MH, Koch MJ, Davies RM, Mellody KT, Kielty CM, Dixon MJ

Dentine dysplasia type II is an autosomal dominant disorder in which mineralization of the dentine of the primary teeth is abnormal. On the basis of the phenotypic overlap between, and shared chromosomal location with, dentinogenesis imperfecta type II, a second disorder of dentine mineralization, it has been proposed that the two conditions are allelic. As recent studies have shown that dentinogenesis imperfecta type II results from mutation of the bicistronic dentine sialophosphoprotein gene (DSPP ), we have tested this hypothesis by sequencing DSPP in a family with a history of dentine dysplasia type II. Our results have shown that a missense change, which causes the substitution of a tyrosine for an aspartic acid in the hydrophobic signal peptide domain of the protein, underlies the phenotype in this family. Biochemical analysis has further demonstrated that this mutation causes a failure of translocation of the encoded proteins into the endoplasmic reticulum, and is therefore likely to lead to a loss of function of both dentine sialoprotein and dentine phosphoprotein.

PMID: 12354781 [PubMed - indexed for MEDLINE]

Intrafibrillar mineral may be absent in dentinogenesis imperfecta type II (DI-II).

J Dent Res. 2001 Jun;80(6):1555-9

Authors: Kinney JH, Pople JA, Driessen CH, Breunig TM, Marshall GW, Marshall SJ

High-resolution synchrotron radiation computed tomography (SRCT) and small-angle x-ray scattering (SAXS) were performed on normal and dentinogenesis imperfecta type II (DI-II) teeth. The SRCT showed that the mineral concentration was 33% lower on average in the DI-II dentin with respect to normal dentin. The SAXS spectra from normal dentin exhibited low-angle diffraction peaks at harmonics of 67.6 nm, consistent with nucleation and growth of the apatite phase within gaps in the collagen fibrils (intrafibrillar mineralization). In contrast, the low-angle peaks were almost non-existent in the DI-II dentin. Crystallite thickness was independent of location in both DI-II and normal dentin, although the crystallites were significantly thicker in DI-II dentin (6.8 nm [SD = 0.5] vs. 5.1 nm [SD = 0.6]). The shape factor of the crystallites, as determined by SAXS, showed a continuous progression in normal dentin from roughly one-dimensional (needle-like) near the pulp to two-dimensional (plate-like) near the dentin-enamel junction. The crystallites in DI-II dentin, on the other hand, remained needle-like throughout. The above observations are consistent with an absence of intrafibrillar mineral in DI-II dentin.

PMID: 11499512 [PubMed - indexed for MEDLINE]

Reduced expression of dentin sialophosphoprotein is associated with dysplastic dentin in mice overexpressing transforming growth factor-beta 1 in teeth.

J Biol Chem. 2001 Apr 6;276(14):11016-20

Authors: Thyagarajan T, Sreenath T, Cho A, Wright JT, Kulkarni AB

Transforming growth factor (TGF)-beta1 is expressed in developing tooth from the initiation stage through adulthood. Odontoblast-specific expression of TGF-beta1 in the tooth continues throughout life; however, the precise biological functions of this growth factor in the odontoblasts are not clearly understood. Herein, we describe the generation of transgenic mice that overexpress active TGF-beta1 predominantly in the odontoblasts. Teeth of these mice show a significant reduction in the tooth mineralization, defective dentin formation, and a relatively high branching of dentinal tubules. Dentin extracellular matrix components such as type I and III collagens are increased and deposited abnormally in the dental pulp, similar to the hereditary human tooth disorders such as dentin dysplasia and dentinogenesis imperfecta. Calcium, one of the crucial inorganic components of mineralization, is also apparently increased in the transgenic mouse teeth. Most importantly, the expression of dentin sialophosphoprotein (dspp), a candidate gene implicated in dentinogenesis imperfecta II (MIM 125420), is significantly down-regulated in the transgenic teeth. Our results provide in vivo evidence suggesting that TGF-beta1 mediated expression of dspp is crucial for dentin mineralization. These findings also provide for the first time a direct experimental evidence indicating that decreased dspp gene expression along with the other cellular changes in odontoblasts may result in human hereditary dental disorders like dentinogenesis imperfecta II (MIM 125420) and dentin dysplasia (MIM 125400 and 125420).

PMID: 11116156 [PubMed - indexed for MEDLINE]

Controversies simmering in the dentin field.

J Dent Res. 2000 Aug;79(8):1544-5

Authors: Simmer JP

PMID: 11023271 [PubMed - indexed for MEDLINE]

The non-collagenous dentin matrix proteins are involved in dentinogenesis imperfecta type II (DGI-II).

J Dent Res. 2000 Mar;79(3):835-9

Authors: Thotakura SR, Mah T, Srinivasan R, Takagi Y, Veis A, George A

Dentinogenesis Imperfecta type II (DGI-II) is a localized form of mesodermal dysplasia of the dentin affecting both the primary and permanent dentitions. This is an autosomal-dominant disease in which there is a disorder in dentin mineralization. Several studies have localized DGI-II to human chromosome 4 in the region 4q 12-21. Many ECM genes-such as OPN, DMP1, DMP2, DMP3 (DSPP), and BSP-have been mapped to the same locus. Biochemical studies indicated that dentin phosphophoryn (DMP2) might be a candidate gene in DGI-II. In this study, we have used histological and RFLP analyses of tissues from a DGI-II-affected patient, as compared with two normal controls, to determine if DMP1, 2, or 3 was linked to DGI-II. The histology of the affected tooth was very different in the DGI-II patient as compared with the normals. In particular, the dentinal tubules in the DGI-II patient were very irregular, which could be the result of perturbations in the process of dentin formation. Patient and control DNA samples were digested with EcoRI or PstI and Southern-hybridized with the DMP1, DMP2, and DMP3 cDNAs. Few differences in the restriction pattern were observed between affected and normal samples for DMP1 and DMP3-3' region (phosphophoryn-like sequences) probes. On the other hand, DMP2 showed a dramatic shift in the restriction pattern in DGI-II. This study suggests that the different restriction enzyme digestion profiles of the DNA from the DGI-II patient, as probed by DMP2, might be related to the defective mineralization of dentin in DGI-II.

PMID: 10765957 [PubMed - indexed for MEDLINE]

Two sibs with an unusual pattern of skeletal malformations resembling osteogenesis imperfecta: a new type of skeletal dysplasia?

J Med Genet. 1999 Nov;36(11):856-8

Authors: Moog U, Maroteaux P, Schrander-Stumpel CT, van Ooij A, Schrander JJ, Fryns JP

We report a 6 year old boy with multiple fractures owing to bilateral, peculiar, wave-like defects of the tibial corticalis with alternative hyperostosis and thinning. Furthermore, he had Wormian bones of the skull, dentinogenesis imperfecta, and a distinct facial phenotype with hypertelorism and periorbital fullness. Collagen studies showed normal results. His sister, aged 2 years, showed the same facial phenotype and dental abnormalities as well as Wormian bones, but no radiographical abnormalities of the tubular bones so far. The mother also had dentine abnormalities but no skeletal abnormalities on x ray. This entity is probably the same as that described in a sporadic case by Suarez and Stickler in 1974. In spite of the considerable overlap with osteogenesis imperfecta (bone fragility, Wormian bones, and dentinogenesis imperfecta), we believe this disorder to be a different entity, in particular because of the unique cortical defects, missing osteopenia, and normal results of collagen studies.

PMID: 10544232 [PubMed - indexed for MEDLINE]

Genetic linkage of the dentinogenesis imperfecta type III locus to chromosome 4q.

J Dent Res. 1999 Jun;78(6):1277-82

Authors: MacDougall M, Jeffords LG, Gu TT, Knight CB, Frei G, Reus BE, Otterud B, Leppert M, Leach RJ

Dentinogenesis imperfecta type III (DGI-III) is an autosomal-dominant disorder of dentin formation which appears in a tri-racial southern Maryland population known as the "Brandywine isolate". This disease has suggestive evidence of linkage to the long arm of human chromosome 4 (LOD score of 2.0) in a family presenting with both juvenile periodontitis and DGI-III. The purpose of this study was to screen a family presenting with only DGI-III to determine if this locus was indeed on chromosome 4q. Furthermore, we wanted to determine if DGI-III co-localized with dentinogenesis imperfecta type II (DGI-II), which has been localized to 4q21-q23. Therefore, a large kindred from the Brandywine isolate was identified, oral examination performed, and blood samples collected from 21 family members. DNA from this family was genotyped with 6 highly polymorphic markers that span the DGI-II critical region of chromosome 4q. Analysis of the data yielded a maximum two-point LOD score of 4.87 with a marker for the dentin matrix protein 1 (DMP1) locus, a gene contained in the critical region for DGI-II. Our results demonstrated that the DGI-III locus is on human chromosome 4q21 within a 6.6 cM region that overlaps the DGI-II critical region. These results are consistent with the hypothesis that DGI-II is either an allelic variant of DGI-III or the result of mutations in two tightly linked genes.

PMID: 10371253 [PubMed - indexed for MEDLINE]

Refinement of the dentinogenesis imperfecta type II locus to an interval of less than 2 centiMorgans at chromosome 4q21 and the creation of a yeast artificial chromosome contig of the critical region.

J Dent Res. 1999 Jun;78(6):1270-6

Authors: Aplin HM, Hirst KL, Dixon MJ

Dentinogenesis imperfecta type II is an autosomal-dominant disorder of dentin formation which has been mapped to the 6.6 centiMorgan D4S2691-D4S2692 interval at human chromosome 4q21. In the current investigation, the use of four short tandem repeat polymorphisms has allowed the critical region to be refined to an interval of less than 2 centiMorgans defined by recombination events in unrelated, affected individuals from two families both of which show independent evidence for linkage to chromosome 4q21. The creation of a yeast artificial chromosome contig of this newly defined interval has allowed us to demonstrate that the critical region encompasses approximately 2 Mb of DNA and that the dentin-specific gene, dentin sialoprotein, maps to this interval within 300 kb of dentin matrix acidic phosphoprotein 1 and bone sialoprotein. Moreover, dentin sialoprotein shows no recombination with the dentinogenesis imperfecta type II phenotype. Dentin sialoprotein is therefore a candidate for the dentinogenesis imperfecta type II locus.

PMID: 10371252 [PubMed - indexed for MEDLINE]

Dentin phosphoprotein and dentin sialoprotein are cleavage products expressed from a single transcript coded by a gene on human chromosome 4. Dentin phosphoprotein DNA sequence determination.

J Biol Chem. 1997 Jan 10;272(2):835-42

Authors: MacDougall M, Simmons D, Luan X, Nydegger J, Feng J, Gu TT

Dentin is the major mineralized extracellular matrix of the tooth. The organic components of dentin consist of type I collagen (90%) with 10% noncollagenous proteins, which are also components of bone. Two dentin proteins, dentin sialoprotein and dentin phosphoprotein, have been shown to be tooth-specific being expressed mostly by odontoblast cells. In this study, we screened a mouse molar tooth library for dentin sialoprotein and dentin phosphoprotein cDNA clones. Analysis of the clones resulted in characterization of a 4420-nucleotide cDNA that contained a 940-amino acid open reading frame. The signal peptide and NH2-terminal sequence was 75% homologous to the cDNA sequence of rat dentin sialoprotein. The continued open reading frame, however, contained a RGD sequence followed by a region of repeated aspartic acid and serine residues. This portion of the protein codes for amino acid sequence consistent with that of dentin phosphoprotein. The noncoding region contains three potential polyadenylation signals, two of which were shown to be utilized. Northern blot analysis indicated the presence of two major transcripts of 4.4 and 2.2 kilobases in odontoblasts. Chromosomal mapping localized the gene to human chromosome 4. These data suggest that the previously identified dentin extracellular matrix proteins, dentin sialoprotein and dentin phosphoprotein, are expressed as a single cDNA transcript coding for a protein that is specifically cleaved into two smaller polypeptides with unique physical-chemical characteristics. Therefore, we propose that the gene be named dentin sialophosphoprotein. The location of the human dentin sialophosphoprotein gene on chromosome 4 suggests that this gene may be a strong candidate gene for the genetic disease dentinogenesis imperfecta type II.

PMID: 8995371 [PubMed - indexed for MEDLINE]

The carboxyl-terminal domain of phosphophoryn contains unique extended triplet amino acid repeat sequences forming ordered carboxyl-phosphate interaction ridges that may be essential in the biomineralization process.

J Biol Chem. 1996 Dec 20;271(51):32869-73

Authors: George A, Bannon L, Sabsay B, Dillon JW, Malone J, Veis A, Jenkins NA, Gilbert DJ, Copeland NG

Phosphophoryns (PPs), a family of Asp and Ser(P)-rich dentin proteins, are considered to be archetypal regulators of several aspects of extracellular matrix (ECM) biomineralization. We have cloned a rat incisor PP gene, Dmp2, from our odontoblast cDNA library and localized it to mouse chromosome 5q21 within 2 centimorgans of Dmp1, another tooth-specific ECM protein. The carboxyl-terminal region of Dmp2 protein (60 residue % Ser, 31 residue % Asp) is divided into two domains, one with unique repetitive blocks of [DSS]n,3</=14, the other with [SD]m = 2,3. Conformational analysis shows the phosphorylated form of the [DS*S*]n repeats to have a unique structure with well defined ridges of phosphates and carboxyls available for counter ion binding. The [S*D]m domains have different phosphate and carboxylate interaction edges and thus different calcium ion and apatite surface binding properties. These two domains and the colocalization of Dmp1 and Dmp2 genes at a position equivalent to the dentinogenesis imperfecta type II location on human 4q21 all suggest that the PPs are indeed involved in some aspect of ECM mineralization.

PMID: 8955126 [PubMed - indexed for MEDLINE]

Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB. Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix.

J Biol Chem. 1996 Aug 30;271(35):21068-74

Authors: Mundlos S, Chan D, Weng YM, Sillence DO, Cole WG, Bateman JF

Osteogenesis imperfecta (OI) type IB is a rare subset of the mildest form of OI, clinically characterized by moderate bone fragility, blue sclera, and dentinogenesis imperfecta. Cultured skin fibroblasts from two unrelated individuals (OI-197 and OI-165) with the typical features of OI type IB produced shortened alpha2(I) chains. Reverse transcription-polymerase chain reaction of the alpha2(I)-cDNA revealed deletions in the triple helical domain of 5 exons (exons 7-11) in OI-197, and 8 exons (exons 10-17) in OI-165. This exon skipping was caused by genomic deletions in one allele of COL1A2 with the breakpoints located in introns 6 and 11 in OI-197, and introns 9 and 17 in OI-165. The secretion and deposition of the mutant collagen into the matrix was measured in vitro in cultures of skin fibroblasts and bone osteoblasts, grown in the presence of ascorbic acid to induce collagen matrix formation and maturation, as well as in collagen extracts from skin and bone. The secretion of mutant collagen was impaired and long term cultures of fibroblasts showed that the mutant collagen was not incorporated into the mature collagenous matrix produced in vitro by skin fibroblasts from both patients. Likewise, the shortened alpha2(I) chain was not demonstrable in skin extracts. In contrast, bone extracts from OI-197 showed the presence of the mutant collagen. This incorporation of the abnormal collagen into the mature matrix was also demonstrated in long term cultures of the patient's osteoblasts. The deposition of the mutant collagen by bone osteoblasts but not by skin fibroblasts demonstrates a tissue specificity in the incorporation of mutant collagen into the matrix which may explain the primary involvement of bone and not skin in these patients.

PMID: 8702873 [PubMed - indexed for MEDLINE]

Immunoreactivity of tenascin-C in dentin matrix in dentinogenesis imperfecta associated with osteogenesis imperfecta.

J Dent Res. 1996 Jan;75(1):581-7

Authors: Lukinmaa PL, Allemanni G, Waltimo J, Zardi L

Osteogenesis imperfecta (OI) is a heterogeneous group of heritable connective tissue disorders, assigned to different mutations in type I collagen genes. A variety of structural abnormalities of dentin have been described in dentinogenesis imperfecta (DI) associated with OI. To clarify further the constitution of the dentin matrix in OI, we immunostained frozen and paraffin sections of deciduous teeth from four patients, each from a different family, with two monoclonal antibodies (MAbs) to the matrix glycoprotein tenascin-C (TN-C). One of the MAbs recognizes an epitope common to all TN-C isoforms (BC-4), and the other is specific for a splicing variant (BC-2). Normal teeth, oral mucosa, and skin were analyzed for comparison. Staining patterns with the two MAbs did not differ markedly. Normal dentin matrix and odontoblasts were lacking reactivity, but the pulp stained clearly. TN-C reactivity was present in the dentin matrix of all teeth obtained from two patients with different OI phenotypes and DI, and in one out of three teeth from one patient who also had DI. The reactivity was distributed in layers, but the staining patterns varied from one patient to another and from tooth to tooth. Intratubular staining seen in a tooth from the patient with clinically and histologically normal teeth was comparable with that present in normal deciduous teeth. The variation in TN-C expression suggests that, besides genetic heterogeneity, epigenetic factors could influence the composition of the dentin matrix in OI.

PMID: 8655763 [PubMed - indexed for MEDLINE]

Genetic mapping of the dentinogenesis imperfecta type II locus.

Am J Hum Genet. 1995 Oct;57(4):832-9

Authors: Crosby AH, Scherpbier-Heddema T, Wijmenga C, Altherr MR, Murray JC, Buetow KH, Dixon MJ

Dentinogenesis imperfecta type II (DGI-II) is an autosomal dominant disorder of dentin formation, which has previously been mapped to chromosome 4q12-21. In the current study, six novel short tandem-repeat polymorphisms (STRPs) have been isolated, five of which show significant evidence of linkage to DGI-II. To determine the order of the STRPs and define the genetic distance between them, nine loci (including polymorphisms for two known genes) were mapped through the CEPH reference pedigrees. The resulting genetic map encompasses 16.3 cM on the sex-averaged map. To combine this map with a physical map of the region, all of the STRPs were mapped through a somatic cell hybrid panel. The most likely location for the DGI-II locus within the fixed marker map is in the D4S2691-D4S2692 interval of 6.6 cM. The presence of a marker that shows no recombination with the DGI-II phenotype between the flanking markers provides an important anchor point for the creation of physical continuity across the DGI-II candidate region.

PMID: 7573043 [PubMed - indexed for MEDLINE]

Altered collagen expression in human dentin: increased reactivity of type III and presence of type VI in dentinogenesis imperfecta, as revealed by immunoelectron microscopy.

J Histochem Cytochem. 1994 Dec;42(12):1593-601

Authors: Waltimo J, Risteli L, Risteli J, Lukinmaa PL

We used transmission immunoelectron microscopy and polyclonal antibodies to study the reactivities of Types III and VI collagen in dentin of normal human permanent and primary teeth and in primary teeth from five patients with dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta and occurring as a single trait. In the normal permanent tooth, reactivity of Type III collagen was occasional and, where present, peritubular. Staining of normal primary teeth was less occasional but still rare, whereas the abnormal dentin stained more uniformly. Atypical, non-striated fibrillar structures that also showed Type III collagen reactivity were observed in dentin of two of the three patients with DI as a single trait. Later, these two patients proved to be first cousins. Unlike antibodies to the N-terminal pro-peptide of Type I pro-collagen, antibodies to the C-terminal telopeptide of Type I collagen, used for comparison stained the affected dentin homogeneously. Reactivity of Type VI collagen, not detected in normal teeth, was seen in the dentin of all abnormal teeth, in association with non-fibrillar delicate material. This study also shows that although readily detectable in dentin affected by DI, Type III collagen is a minor constituent of normal human dentin matrix.

PMID: 7983359 [PubMed - indexed for MEDLINE]

In situ localization and chromosomal mapping of the AG1 (Dmp1) gene.

J Histochem Cytochem. 1994 Dec;42(12):1527-31

Authors: George A, Gui J, Jenkins NA, Gilbert DJ, Copeland NG, Veis A

Dentinogenesis is being used as a model for understanding the biomineralization process. The odontoblasts synthesize a structural matrix comprised of Type I collagen fibrils which define the basic architecture of the tissue. The odontoblasts also synthesize and deliver a number of dentin-specific acidic macromolecules into the extracellular compartment. These acidic macromolecules may be involved in regulating the ordered deposition of hydroxyapatite crystals within the matrix. AG1 is the first tooth-specific acidic macromolecule to have been cloned and sequenced. To identify which cells of the rat incisor pulp/odontoblast complex were responsible for synthesis of AG1, in situ hybridization was used. Digoxigenin labeled sense and anti-sense AG1 riboprobes were prepared. The AG1 mRNA was found to be expressed in the mature secretory odontoblasts. Neither pulp cells nor pre-odontoblasts showed any staining with the anti-sense probes. Chromosomal localization studies placed the AG1 gene on mouse chromosome 5q21, in tight linkage with Fgf5. AG1 has been renamed Dmp1 (dentin matrix protein 1) in accordance with present chromosomal nomenclature. Mouse 5q21 corresponds to the 4q21 locus in humans. This is the locus for the human tooth mineralization disorder dentinogenesis imperfecta Type II (DI-II). These data suggest that the Dmp1 gene is involved in mineralization and is a candidate gene for DI-II.

PMID: 7983353 [PubMed - indexed for MEDLINE]

ED-A region-containing isoform of cellular fibronectin is present in dentin matrix in dentinogenesis imperfecta associated with osteogenesis imperfecta.

J Dent Res. 1994 Jun;73(6):1187-96

Authors: Lukinmaa PL, Vaheri A

To elucidate the defective dentin formation in osteogenesis imperfecta (OI), we analyzed the expression of selected fibronectin (FN) isoforms in the dentin matrix of a patient with dentinogenesis imperfecta (DI) associated with OI, and in normal teeth. Frozen tooth sections were immunostained with three monoclonal antibodies (MAbs). The MAb recognizing the major cell-binding region (f-33), shared by plasma FN (pFN) and cellular FN (cFN), stained the pulp of normal adult permanent teeth intensely, while no reactivity was present in predentin, (demineralized) dentin, or dental cementum. The periodontal ligament stained unevenly. The dentin matrix of the patient with OI displayed reactive zones, alternating layerwise or concentrically with non-reactive ones. Staining throughout the connective tissue of adult oral mucosa, analyzed for the form of FN present, was intense, and in dermis, which was also studied, it was moderate. Reactivities in dental tissues with the MAb specific for the ED-A region (IST-9), included in cFN but not pFN, were similar to those with MAb f-33. The mucosal connective tissue stained weakly and dermis was negative, except that nerves and endothelia of some large blood vessels stained clearly. The MAb specific for the ED-B segment (BC-1), also included in cFN only, did not stain any of the tissues analyzed. The results suggest that, unlike mucosal and dermal FNs, FNs in the dental tissues are largely cellular, and also that dentin formation in OI may be completed by successive generations of pulpal fibroblasts differentiated into hard-tissue-forming cells.

PMID: 8046108 [PubMed - indexed for MEDLINE]

Dentin phosphoprotein gene locus is not associated with dentinogenesis imperfecta types II and III.

Am J Hum Genet. 1992 Jan;50(1):190-4

Authors: MacDougall M, Zeichner-David M, Murray J, Crall M, Davis A, Slavkin H

Dentinogenesis imperfecta (DGI) is an autosomal dominant inherited dental disease which affects dentin production and mineralization. Genetic linkage studies have been performed on several multigeneration informative kindreds. These studies determined linkage between DGI type II and III and group-specific component (vitamin D-binding protein). This gene locus has been localized to the long arm of human chromosome 4 in the region 4q11-q21. Although this disease has been mapped to chromosome 4, the defective gene product is yet to be determined. Biochemical studies have suggested abnormal levels of dentin phosphoprotein (DPP) associated with DGI type II. This highly acidic protein is the major noncollagenous component of dentin, being solely expressed by the ectomesenchymal derived odontoblast cells of the tooth. The purpose of the present study was to establish whether DPP is associated with DGI types II and III, by using molecular biology techniques. The strategy was to use a synthetic degenerative DPP oligonucleotide probe to map this sequence to the long arm of human chromosome 4, 4q13-q21, by using somatic cell hybrids. Our results indicated that DPP is not localized to any region of human chromosome 4, thus suggesting that the DPP gene is not directly associated with DGI type II or DGI type III. Our data do not exclude the possibility that other proteins associated with DPP posttranslational modifications might be responsible for this genetic disease.

PMID: 1729887 [PubMed - indexed for MEDLINE]

Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta.

Am J Hum Genet. 1990 May;46(5):975-82

Authors: Wenstrup RJ, Willing MC, Starman BJ, Byers PH

We reviewed clinical and biochemical findings from 132 probands with nonlethal forms of osteogenesis imperfecta (OI) whose fibroblasts were sent to the University of Washington for diagnostic studies in the years 1981-87. In cells from 86% of probands with nonlethal OI we identified biochemical alterations compatible with heterozygosity for a mutation that affected expression or structure of alpha chains of type I procollagen. We observed two major biochemical phenotypes. Cells from 40 probands (group A) secreted about half the normal amount of normal type I procollagen and no identifiable abnormal molecules; these patients were generally of normal stature, rarely had bone deformity or dentinogenesis imperfecta, and had blue sclerae. Cells from 74 probands (group B) produced and secreted normal and abnormal type I procollagen molecules; these patients were usually short and had bone deformity and dentinogenesis imperfecta, and many had grey or blue-grey sclerae. In cells from an additional 18 probands (group C) we were unable to identify altered type I procollagen synthesis or structure. Detection of these abnormalities has value in the determination of mode of inheritance and in the prediction of clinical severity.

PMID: 2339695 [PubMed - indexed for MEDLINE]

Osteogenesis imperfecta in the differential diagnosis of child abuse.

BMJ. 1989 Dec 9;299(6713):1451-4

Authors: Paterson CR, McAllion SJ

PMID: 2514833 [PubMed - indexed for MEDLINE]

Molecular heterogeneity in the mild autosomal dominant forms of osteogenesis imperfecta.

Am J Hum Genet. 1984 Nov;36(6):1172-9

Authors: Tsipouras P, B&#xF8;rresen AL, Dickson LA, Berg K, Prockop DJ, Ramirez F

Mild osteogenesis imperfecta (OI type I and OI type IV) is characterized by postnatal onset of fractures, absence of skeletal deformity, presenile hearing loss with or without blue sclerae, and dentinogenesis imperfecta. Using one common DNA polymorphism associated with the pro alpha 2(I) human collagen gene, we found genetic heterogeneity in this disorder. In three families, the OI phenotype segregated independently of the DNA polymorphism, whereas in one family, the OI phenotype cosegregated with a DNA polymorphism in a manner suggesting linkage. Use of DNA polymorphisms associated with both type I procollagen genes should provide a tool to unravel the molecular heterogeneity of various heritable disorders of the connective tissue.

PMID: 6097110 [PubMed - indexed for MEDLINE]

Osteogenesis imperfecta with dominant inheritance and normal sclerae.

J Bone Joint Surg Br. 1983 Jan;65(1):35-9

Authors: Paterson CR, McAllion S, Miller R

Most patients with dominantly inherited osteogenesis imperfecta have blue sclerae and relatively mild symptoms. However, in a small group of families the patients have normal sclerae and this disorder has been classified as Type 4 osteogenesis imperfecta. This paper reports the clinical and radiographical features of 48 patients from 16 families with Type 4 osteogenesis imperfecta and compares the findings with those of the classical disorder with blue sclerae (Type 1 osteogenesis imperfecta). The two types are similar in usually causing a mild disease but with a wide range of severity, and in both types the rate of fracture declines in adolescence. There are, however, some significant differences apart from the colour of the sclerae. In Type 4 the first fracture more commonly occurs at birth, dentinogenesis imperfecta is more frequent than in Type 1 and bruising and nose-bleeds are less common. As in Type 1, the radiographic appearances of the bones may be normal. It is important that Type 4 osteogenesis imperfecta should be recognised because of the need for competent genetic counselling, because the management may be different from that appropriate for Type 1 and because it may be mistaken for idiopathic juvenile osteoporosis or child abuse.

PMID: 6822598 [PubMed - indexed for MEDLINE]

The inorganic phase in dentinogenesis imperfecta.

J Dent Res. 1981 Sep;60(9):1655-60

Authors: Kerebel B, Daculsi G, Menanteau J, Kerebel LM

The inorganic phase in dentin with dentinogenesis imperfecta was investigated, using the correlated techniques of high resolution TEM, X-ray diffraction analyses, infrared absorption spectroscopy, thermogravimetry, and chemical and electron microprobe analyses. It was shown that crystallites in dentin with dentinogenesis imperfecta are of normal size (from 3 to 6 lattice planes thick), but less numerous than in normal dentin. Electron microprobe analyses indicated significant differences in the mineral content of dentin with dentinogenesis imperfecta compared to normal dentin. A higher Ca/P ratio, a loss in Ca and P, and a severe significant loss in Mg, corroborated by chemical analyses, were recorded. The main component of the inorganic phase in dentin with dentinogenesis imperfecta was found to be poorly crystallized carbonated apatite. It is suggested that the water content, greatly increased in dentin with dentinogenesis imperfecta, is at least partly related to lattice water tightly bound to the inorganic phase.

PMID: 6943158 [PubMed - indexed for MEDLINE]

A new look at osteogenesis imperfecta. A clinical, radiological and biochemical study of forty-two patients.

J Bone Joint Surg Br. 1975 Feb;57(1):2-12

Authors: Bauze RJ, Smith R, Francis MJ

In a clinical, radiological and biochemical study of forty-two patients from Oxford with osteogenesis imperfecta, it was found that patients could be divided simply into mild, moderate and severe groups according to deformity of long bones. In the severe group (seventeen patients) a family history of affected members was uncommon and fractures began earlier and were more frequent than in the mild group (twenty-two patients); sixteen patients in the severe group had scoliosis and eleven had white sclerae; no patients in the mild group had white sclerae or scoliosis. Radiological examination of the femur showed only minor modelling defects in patients in the mild group, whereas in the severe group five distinct appearances of bone (thin, thick, cystic and buttressed bones, and those with hyperplastic callus) were seen. The polymeric (structural) collagen from skin was unstable to depolymerisation in patients in the severe group, but normal in amount, whereas the reverse was found in the mild group. This division according to long bone deformity may provide, a basis for future research more useful than previous classifications.

PMID: 1117018 [PubMed - indexed for MEDLINE]

Dentinogenesis imperfecta: genetic variations in a six-generation family.

J Dent Res. 1969 Nov-Dec;48(6):1196-9

Authors: Bixler D, Conneally PM, Christen AG

PMID: 5262382 [PubMed - indexed for MEDLINE]

Blue sclerae and keratoglobus. Ocular signs of a systemic connective tissue disorder.

Br J Ophthalmol. 1969 Jan;53(1):53-8

Authors: Hyams SW, Kar H, Neumann E

PMID: 5775573 [PubMed - indexed for MEDLINE]

Oral disorders associated with ocular disease. II. Disorders affecting dentition.

Br J Ophthalmol. 1967 Apr;51(4):284-5

Authors: Harcourt B

PMID: 4960351 [PubMed - indexed for MEDLINE]

Polarized light and microradiographic study of dental tissues in dentinogenesis imperfecta.

J Dent Res. 1967 Mar-Apr;46(2):434-41

Authors: Soni NN, Henry JL, Silberkweit M, Coombs BP

PMID: 5228077 [PubMed - indexed for MEDLINE]