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DSPP Function, Pathophysiology, and Genetic Diagnosis

DSPP 功能、病理生理学和遗传诊断

基本信息

批准号：
10448405
负责人：
JAMES P SIMMER
金额：
$ 47.51万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448405
关键词：
Affect Algorithms Amino Acids C-terminal COL1A1 gene COL1A2 gene Cells Cellular Stress Clinical Collagen Gene Collagen Type I DSPP gene Defect Dental Dental Enamel Dentin Dentin Dysplasia Dentin Formation Dentinogenesis Dentinogenesis Imperfecta Diagnosis Disease Dominant-Negative Mutation Endoplasmic Reticulum Etiology Family Fracture Frameshift Mutation Functional disorder Gene Mutation Genes Genetic Goals Growth Health Human Incisor Individual Inheritance Patterns Inherited Ions Knock-in Mouse Knockout Mice Label Life Mandible Measures Mediating Medical Methods Minerals Mus Mutation Odontoblasts Organelles Osteogenesis Imperfecta Pathologic Pathology Patients Pattern Persons Pharmacology Phenotype Process Proteins Protocols documentation Reporting Reproducibility Research Resolution Risk Role Scanning Electron Microscopy Symptoms Syndrome Testing Therapeutic Time Tooth structure Toxic effect adduct bone bone fragility causal variant clinical phenotype disease-causing mutation endoplasmic reticulum stress gain of function genetic disorder diagnosis genetic testing human disease improved in vivo in vivo evaluation malformation microscopic imaging mineralization mouse model mutant recruit response

项目摘要

Hereditary Dentin Defects (HDD) affect 1 in 8,000 people. The genetic causes of most HDD correlate with the dysfunction of dentin proteins: type I collagen and dentin sialophosphoprotein (DSPP). All DSPP mutations reported to date show a dominant pattern of inheritance. This is because DSPP mutations manifest their phenotype through a dominant negative or gain of function mechanism—not by haplo- insufficiency. Reducing the normal amount of DSPP by half, as in Dspp heterozygous mice, does not cause dentin malformations. Dspp-/- null mice show a severe phenotype due to the absence of DSPP—not by the autosomal dominant pathological mechanism that causes HDD in humans. This distinction is important. Therapeutically, HDD in the absence of Dspp-/- could be reversed by restoring DSPP expression, whereas human HDD caused by DSPP mutations could not be restored in this way because the condition is not due to a lack of DSPP protein, but rather, is due to the pathological effects of aberrant DSPP in odontoblasts. This proposal “DSPP Function, Pathophysiology, and Genetic Diagnosis” seeks to improve our under- standings of 1) DSPP-derived proteins during normal dentinogenesis, 2) the pathological mechanism of Dspp -1 frameshift mutations, and 3) to develop a practical approach for HDD genetic testing to specifically identify the causative mutation and establish a definitive diagnosis. Three Specific Aims are proposed: SA1: Determine the role of DSPP-derived proteins during initial dentin mineral formation and coalescence by characterizing early dentin mineralization in Dspp+/+, Dspp-1fs/-1fs, Dspp-2fs/-2fs and Dspp-/- mice. SA2: Localize the DSPP -1 frameshift protein in vivo to determine where it accumulates and causes odontoblast cell pathology. SA3: Improve the diagnosis and management of HDDs by establishing an efficient genetic testing algorithm (sequence of actions that identifies the exact genetic cause of HDD in a given individual). Strategy: We hypothesize that DSPP helps initiate the mineralization of dentin calcospherites and promotes their growth and coalescence into a continuous mineral layer. By characterizing and comparing early dentin mineralization in Dspp+/+, Dspp-/-, and Dspp-2fs/-2fs mice using Focus Ion Beam Scanning Electron Microscopy (FIB-SEM), we can determine if dentin sialoprotein (DSP) or dentin phosphoprotein (DPP) is promoting the initiation and/or coalescence of dentin. We hypothesize that DSPP -1 frameshift mutations cause odontoblast cell pathology, possibly through ER stress. We test this hypothesis using Dspp -1 frameshift knockin mice that closely mimic human disease. Odontoblast pathology is assessed by FIB-SEM and TEM double immunogold labeling for the mutant protein and organelle markers in vivo. To improve the diagnosis and management of HDD, we apply a genetic testing algorithm to recruited HDD families to optimize its reproducibility and efficiency in identifying the underlying disease-causing mutations.

遗传性牙本质缺陷（HDD）影响8,000人中有1人。大多数HDD的遗传原因与

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome.

釉质肾综合征牙髓组织 FAM20A 突变及转录组分析

DOI：
10.1111/iej.13928
发表时间：
2023
期刊：
International endodontic journal
影响因子：
5
作者：
Wang,Shih-Kai;Zhang,Hong;Wang,Yin-Lin;Lin,Hung-Ying;Seymen,Figen;Koruyucu,Mine;Wright,JTimothy;Kim,Jung-Wook;Simmer,JamesP;Hu,JanC-C
通讯作者：
Hu,JanC-C

The Modified Shields Classification and 12 Families with Defined DSPP Mutations.

DOI：
10.3390/genes13050858
发表时间：
2022-05-12
期刊：
Genes
影响因子：
3.5
作者：
通讯作者：

Mouse Dspp frameshift model of human dentinogenesis imperfecta.

DOI：
10.1038/s41598-021-00219-4
发表时间：
2021-10-19
期刊：
Scientific reports
影响因子：
4.6
作者：
Liang T;Hu Y;Zhang H;Xu Q;Smith CE;Zhang C;Kim JW;Wang SK;Saunders TL;Lu Y;Hu JC;Simmer JP
通讯作者：
Simmer JP