The Modified Shields Classification and 12 Families with Defined DSPP Mutations

Simmer, James P.; Zhang, Hong; Moon, Sophie J. H.; Donnelly, Lorenza A.; Lee, Yuan-Ling; Seymen, Figen; Koruyucu, Mine; Chan, Hui-Chen; Lee, Kevin Y.; Wu, Szu-Yuan; Hsiang, Chia-Lan; Tsai, Anthony; Slayton, Rebecca L.; Morrow, Melissa M.; Wang, Shih‐Kai; Shields, Edward D.; Hu, Jan C.‐C.

doi:10.3390/genes13050858

Cited by 8 publications

(32 citation statements)

References 97 publications

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“…DSPP mutations in humans are associated with dentinogenesis imperfecta type II (DGI-II, OMIM 125490) and DGI-III (OMIM 125500), as well as dentin dysplasia type II (DD-II, OMIM 125420) and DD-I (MIM 125400) [ 269 , 270 , 271 , 272 , 273 ]. These hereditary dentin diseases are the most common dentin genetic diseases.…”

Section: Bmp Downstream Gene Expression During Tooth Developmentmentioning

confidence: 99%

BMP Signaling Pathway in Dentin Development and Diseases

Liu

Goldman

MacDougall

et al. 2022

Cells

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BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.

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Section: Bmp Downstream Gene Expression During Tooth Developmentmentioning

confidence: 99%

BMP Signaling Pathway in Dentin Development and Diseases

Liu

Goldman

MacDougall

et al. 2022

Cells

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“…The DSPP protein is cleaved following its secretion 3 into the N-terminal dentin sialoprotein (DSP) and the C-terminal dentin phosphoprotein (DPP) 4 . Mutations in dentin sialophosphoprotein ( DSPP ) cause non-syndromic autosomal dominant dentinogenesis imperfecta (DGI) 5 , 6 . Disease-causing DSPP mutations fall predominately into two categories: (1) 5’ mutations altering the first three amino acid residues following the signal peptide 7 , i.e.…”

Section: Introductionmentioning

confidence: 99%

“…isoleucine-proline-valine (IPV), and (2) 3’ -1 frameshift mutations that replace the downstream repetitive, hydrophilic and acidic wild type (WT) DPP sequence with a longer, hydrophobic one 8 – 10 . For diagnostic purposes the Shields classification 11 was recently modified to correlate the 5’ and 3’ DSPP mutations with a diagnosis of DGI-III and DGI-II, respectively 6 .…”

Section: Introductionmentioning

confidence: 99%

“…Previously we generated two Dspp -knockin mouse models: Dspp P19L mice 12 homologous to the p.Pro17Leu mutation in humans 6 , 13 – 15 representing the 5’ group of DSPP mutations, and Dspp −1fs mice 16 representing the 3’ group of human DSPP -1 frameshift mutations. Both mice displayed dental defects inherited in an autosomal dominant pattern and showed intracellular accumulation of mutated DSPP but varied in their dental phenotypes and cell abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…Given the multiple clinical designations of inherited conditions caused by mutations in DSPP 5 , 6 , 11 and their correlation with the severity of the patient clinical findings and their prognosis, we further investigate the disease mechanisms underlying the two distinct groups of inherited dentin disorders resulting from mutations in different regions of the same gene in Dspp P19L and Dspp −1fs mice.…”

Section: Introductionmentioning

confidence: 99%

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Dentin defects caused by a Dspp−1 frameshift mutation are associated with the activation of autophagy

Liang

Smith

et al. 2023

Sci Rep

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Dentin sialophosphoprotein (DSPP) is primarily expressed by differentiated odontoblasts (dentin-forming cells), and transiently expressed by presecretory ameloblasts (enamel-forming cells). Disease-causing DSPP mutations predominantly fall into two categories: 5’ mutations affecting targeting and trafficking, and 3’ − 1 frameshift mutations converting the repetitive, hydrophilic, acidic C-terminal domain into a hydrophobic one. We characterized the dental phenotypes and investigated the pathological mechanisms of DsppP19L and Dspp−1fs mice that replicate the two categories of human DSPP mutations. In DsppP19L mice, dentin is less mineralized but contains dentinal tubules. Enamel mineral density is reduced. Intracellular accumulation and ER retention of DSPP is observed in odontoblasts and ameloblasts. In Dspp−1fs mice, a thin layer of reparative dentin lacking dentinal tubules is deposited. Odontoblasts show severe pathosis, including intracellular accumulation and ER retention of DSPP, strong ubiquitin and autophagy activity, ER-phagy, and sporadic apoptosis. Ultrastructurally, odontoblasts show extensive autophagic vacuoles, some of which contain fragmented ER. Enamel formation is comparable to wild type. These findings distinguish molecular mechanisms underlying the dental phenotypes of DsppP19L and Dspp−1fs mice and support the recently revised Shields classification of dentinogenesis imperfecta caused by DSPP mutations in humans. The Dspp−1fs mice may be valuable for the study of autophagy and ER-phagy.

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Identification of DSPP novel variants and phenotype analysis in dentinogenesis dysplasia Shields type II patients

Cao

Yan

et al. 2023

Clin Oral Invest

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Objectives: To investigate the genetic causes and characteristics of teeth of dentin dysplasia Shields Type-II(DD-II) in three Chinese families.Materials and Methods: Three Chinese families affected with DD-II were collected. The whole-exome sequencing(WES) and whole-genome sequencing(WGS) were conducted to screen for variations, and sanger sequencing was used to verify mutation sites. The physical and chemical characteristics of the affected teeth including tooth structure, hardness, mineral content and ultrastructure were investigated.Results: A novel frameshift deletion mutation c.1871_1874del(p.Ser624fs) in DSPP was found in family A and family B, while no pathogenic mutation was found in family C. The affected teeth's pulp cavities were obliterated, and the root canals were smaller than normal teeth and irregularly distributed comprising a network. The patients' teeth also had reduced dentin hardness and highly irregular dentinal tubules. The Mg content of the teeth was signi cantly higher than the controls but the Na content was obviously lower than the controls.Conclusions: A novel frameshift deletion mutation c.1871_1874del(p.Ser624fs) in the DPP region of the DSPP gene caused DD-II. The DD-II teeth demonstrated compromised mechanical properties and changed ultrastructure, suggesting an impaired function of DPP. Our ndings expanded the mutational spectrum of DSPP gene and strengthen the understanding of clinical phenotypes related to the frameshift deletion in the DPP region of the DSPP gene.Clinical Relevance: DSPP mutation can cause the characteristics of the affected teeth including tooth structure, hardness, mineral content and ultrastructure.

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The Modified Shields Classification and 12 Families with Defined DSPP Mutations

Cited by 8 publications

References 97 publications

BMP Signaling Pathway in Dentin Development and Diseases

BMP Signaling Pathway in Dentin Development and Diseases

Dentin defects caused by a Dspp−1 frameshift mutation are associated with the activation of autophagy

Identification of DSPP novel variants and phenotype analysis in dentinogenesis dysplasia Shields type II patients

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