Mutation identification of the DSPP in a Chinese family with DGI-II and an up-to-date bioinformatic analysis

Li, Daxu; Du, Xiang; Zhang, Rui; Shen, Bo; Huang, Yunfei; Valenzuela, Robert K.; Wang, Bin; Zhao, Huaxiang; Liu, Zunwei; Li, Jianjun; Zhao, Xu; Gao, Linghan; Ma, Jianhua

doi:10.1016/j.ygeno.2012.01.006

Cited by 18 publications

(20 citation statements)

References 35 publications

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“…This suggests that the mutation is not a common variant of the DSPP gene. The same mutation has been recently identified in a Chinese family [25]. This mutation changes the proline residue at the +2-position (P2′) from the signal peptide cleavage site to the leucine residue (p.P17L).…”

Section: Resultsmentioning

confidence: 70%

“…DSPP is rapidly cleaved by proteases into three major proteins: dentin sialoprotein (DSP), dentin glycoprotein (DGP), and dentin phosphoprotein (DPP) [3, 4]. Mutations in the DSPP gene have been identified to cause DGI type II, III, and DD type II [5–25]. Therefore, these diseases are not separate, but are allelic with differing severity [2].…”

Section: Introductionmentioning

confidence: 99%

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ADSPPMutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect

Lee

Song

et al. 2013

BioMed Research International

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Mutations in the DSPP gene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations of DSPP affecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER). In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries of DSPP gene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L) in exon 2 of the DSPP gene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.

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Section: Resultsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

ADSPPMutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect

Lee

Song

et al. 2013

BioMed Research International

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“…Both of the DSP aa 363–458 and OclnL2 aa 194–241 are high homologous across species lines. In human, the mutation of DSP at codon 45 (c.133C > T, p.Q45X) introduces a premature terminal signal and would results in a truncated protein without the COOH-terminal DSP domain 21, 25, 64, 65 . As the mouse COOH-terminal DSP domain aa 363–458 is highly homologous to the human COOH-terminal DSP domain aa 374–469 66 and this domain regulates dental mesenchymal cell lineages and mineralization through Ocln-FAK signal.…”

Section: Discussionmentioning

confidence: 99%

“…DPP contains an RGD domain, acting as a ligand, and binds to integrin as well as triggers intracellular signals via DPP-RGD/integrin-αvβ3 interactions 23, 24 . By contrast, DSP lacks a RGD domain 9 , and many DSPP gene mutations occur in DSP region 19, 20, 25 . DSP and peptides derived from DSP are able to regulate gene expression and protein phosphorylation as well as induce dental primary/stem cell differentiation 9, 16, 26 .…”

Section: Introductionmentioning

confidence: 99%

Dentin sialoprotein facilitates dental mesenchymal cell differentiation and dentin formation

Chen

et al. 2017

Sci Rep

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Dentin sialoprotein (DSP) is a dentin extracellular matrix protein. It is involved in dental mesenchymal cell lineages and dentin formation through regulation of its target gene expression. DSP mutations cause dentin genetic diseases. However, mechanisms of DSP in controlling dental mesenchymal cell differentiation are unknown. Using DSP as bait, we screened a protein library from mouse odontoblastic cells and found that DSP is a ligand and binds to cell surface receptor, occludin. Further study identified that the C-terminal DSP domainaa 363–458 interacts with the occludin extracellular loop 2aa 194–241. The C-terminal DSP domain induced phosphorylation of occludin Ser490 and focal adhesion kinase (FAK) Ser722 and Tyr576. Coexpression of DSP, occludin and FAK was detected in dental mesenchymal cells during tooth development. Occludin physically interacts with FAK, and occludin and FAK phosphorylation can be blocked by DSP and occludin antibodies. This DSP domain facilitates dental mesenchymal cell differentiation and mineralization. Furthermore, transplantation and pulp-capping procedures revealed that this DSP domain induces endogenous dental pulp mesenchymal cell proliferation, differentiation and migration, while stimulating blood vessel proliferation. This study elucidates the mechanism of DSP in dental mesenchymal lineages and implies that DSP may serve as a therapeutic agent for dentin-pulp complex regeneration in dental caries.

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“…Most disease-causing mutations in the DSP coding region result in a change within the “IPV” motif and are referred to as “IPV mutations”, such as the substitution of the proline (P) residue with leucine (L) (Li et al, 2012). In addition, skipping exon 3 due to a splice site mutation may also be classified as an IPV mutation (von Marschall et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The LPV Motif Is Essential for the Efficient Export of Secretory DMP1 From the Endoplasmic Reticulum

et al. 2015

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Dentin matrix protein 1 (DMP1) is found abundantly in the extracellular matrices of bone and dentin. Secretory DMP1 begins with a tripeptide of leucine-proline-valine (LPV) after the endoplasmic reticulum (ER)-entry signal peptide is cleaved. The goal of this study was to determine the role of the LPV motif in the secretion of DMP1. A series of DNA constructs was generated to express various forms of DMP1 with or without the LPV motif. These constructs were transfected into a preosteoblast cell line, the MC3T3-E1 cells, and the subcellular localization and secretion of various forms of DMP1 were examined by immunofluorescent staining and Western-blotting analyses. Immunofluorescent staining showed that the LPV-containing DMP1 variants were primarily localized in the Golgi complex, whereas the LPV-lacking DMP1 variants were found abundantly within the ER. Western-blotting analyses demonstrated that the LPV-containing DMP1 variants were rapidly secreted from the transfected cells, as they did not accumulate within the cells, and the amounts increased in the conditioned media over time. In contrast, the LPV-lacking DMP1 variants were predominantly retained within the cells, and only small amounts were secreted out of the cells over time. These results suggest that the LPV motif is essential for the efficient export of secretory DMP1 from the ER to the Golgi complex.

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Mutation identification of the DSPP in a Chinese family with DGI-II and an up-to-date bioinformatic analysis

Cited by 18 publications

References 35 publications

ADSPPMutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect

ADSPPMutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect

Dentin sialoprotein facilitates dental mesenchymal cell differentiation and dentin formation

The LPV Motif Is Essential for the Efficient Export of Secretory DMP1 From the Endoplasmic Reticulum

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