Haploinsufficiency of Dspp Gene Causes Dentin Dysplasia Type II in Mice

Shi, Ce; Ma, Ning; Zhang, Wei; Ye, Jiapeng; Shi, Haibo; Xiang, Danwei; Wu, Chunyue; Song, Lina; Zhang, Ning; Liu, Qilin

doi:10.3389/fphys.2020.593626

Cited by 6 publications

(5 citation statements)

References 32 publications

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“…To understand the specific functions of DSPP on condyles, we employed Dspp +/– mice to observe long-term DSPP haplodeficency on the condyle, because previous studies reported that Dspp +/– mice have no teeth phenotype [ 36 , 37 ]. Although recently we found that Dspp +/– mice exhibited teeth phenotype like human DD-II, and had mild periodontitis [ 20 ], Our findings (Fig. 2 b) showed that the tooth phenotype was too weak to impact occlusal balance compared with Dspp −/− mice at the age of 12 months.…”

Section: Discussioncontrasting

confidence: 51%

“…Dspp −/− mice exhibited defective mineralization in long bone, alveolar bone as well as skull bone [ 16 , 17 , 38 ]. Besides the subchondral bone, Dspp +/– mice also bear the low quality of bone in the whole body, including alveolar bone [ 20 ] and long bone (data not shown). Dspp mutation, in the heterozygous background, in patients with DGI have compromised alveolar bone cells [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice

Liu,

Zhao,

Shi

et al. 2024

BMC Oral Health

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Background Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. Materials and methods To determine whether Dspp+/– mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/–, and Dspp homozygous (Dspp−/−) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/– mice over time, condyles of Dspp+/– and WT mice were analyzed radiologically, histologically, and immunohistochemically. Results Micro-CT and histomorphometric analyses revealed that Dspp+/– and Dspp−/− mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp−/− mice which exhibited tooth loss, Dspp+/– mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/– mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/– mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. Conclusions Dspp+/– mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice

Liu,

Zhao,

Shi

et al. 2024

BMC Oral Health

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“…The pattern of mutations strongly supports the conclusion that simple loss-of-function mutations do not cause dominant dentin malformations in humans 14 . In mice, Dspp heterozygotes show either no dentin phenotype 10 , or mild dentin defects not evident until old age 15 .…”

Section: Introductionmentioning

confidence: 99%

Mouse Dspp frameshift model of human dentinogenesis imperfecta

Liang

Zhang

et al. 2021

Sci Rep

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Non-syndromic inherited defects of tooth dentin are caused by two classes of dominant negative/gain-of-function mutations in dentin sialophosphoprotein (DSPP): 5′ mutations affecting an N-terminal targeting sequence and 3′ mutations that shift translation into the − 1 reading frame. DSPP defects cause an overlapping spectrum of phenotypes classified as dentin dysplasia type II and dentinogenesis imperfecta types II and III. Using CRISPR/Cas9, we generated a Dspp−1fs mouse model by introducing a FLAG-tag followed by a single nucleotide deletion that translated 493 extraneous amino acids before termination. Developing incisors and/or molars from this mouse and a DsppP19L mouse were characterized by morphological assessment, bSEM, nanohardness testing, histological analysis, in situ hybridization and immunohistochemistry. DsppP19L dentin contained dentinal tubules but grew slowly and was softer and less mineralized than the wild-type. DsppP19L incisor enamel was softer than normal, while molar enamel showed reduced rod/interrod definition. Dspp−1fs dentin formation was analogous to reparative dentin: it lacked dentinal tubules, contained cellular debris, and was significantly softer and thinner than Dspp+/+ and DsppP19L dentin. The Dspp−1fs incisor enamel appeared normal and was comparable to the wild-type in hardness. We conclude that 5′ and 3′ Dspp mutations cause dental malformations through different pathological mechanisms and can be regarded as distinct disorders.

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“…There are complexities in the genotype–phenotype correlations of DPP mutations. Haploinsufficiency, hydrophobicity, and WT‐MUT (wild‐type‐mutant) DSPP interaction in the rough endoplasmic reticulum (rER) may be factors that affect the disease phenotype (Lee, Kang, et al, 2011; Lee, Lee, et al, 2011; Shi et al, 2020; von Marschall et al, 2012). The closer the frameshift sites are to the N‐terminus, the more likely the mutations would result in completely disordered protein sequences and a shorter Ca 2+ ‐binding domain in capturing normal DSPP protein within the rER (Lee, Kang, et al, 2011; Lee, Lee, et al, 2011).…”

Section: Correlation Between the Mutation Sites And The Severity Of D...mentioning

confidence: 99%

A novel DSPP frameshift mutation causing dentin dysplasia type 2 and disease management strategies

et al. 2023

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The present study aims to investigate the mutation in a Chinese family with dentin dysplasia type II (DD‐II) and to summarize mutation hotspots, clinical manifestations, and disease management strategies. Phenotype analysis, clinical intervention, mutation screening, and cosegregation analysis within the enrolled family were performed. A summary of the reported mutations in the dentin phosphoprotein (DPP) region of dentin sialophosphoprotein (DSPP) was analyzed. Pathogenicity prediction analysis of the physical properties and function of DSPP variants was performed by bioinformatic processing. Clinical management strategies are discussed. A novel pathogenic mutation (c.2035delA) in the DPP region of DSPP was identified, which was cosegregated in the family. The immature permanent teeth of patients with DD‐II presented with X‐shaped root canal phenotypes. Most of the identified mutations for DD‐II were clustered in the DPP region between nucleotides 1686–2134. Points of differential diagnosis, clinical interventions, and management strategies are proposed. This study revealed a novel DSPP frameshift mutation and presented new clinical features of DD‐II. The locus involving nucleotides 1686–2134 of DSPP may represent a mutational hotspot for the disease. Appropriate management of DD‐II at different stages is important to avoid the development of secondary dental lesions.

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Haploinsufficiency of Dspp Gene Causes Dentin Dysplasia Type II in Mice

Cited by 6 publications

References 32 publications

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice

Mouse Dspp frameshift model of human dentinogenesis imperfecta

A novel DSPP frameshift mutation causing dentin dysplasia type 2 and disease management strategies

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