# DSPP Function, Pathophysiology, and Genetic Diagnosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $479,922

## Abstract

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.

## Key facts

- **NIH application ID:** 10167682
- **Project number:** 5R01DE027675-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JAMES P SIMMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $479,922
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167682

## Citation

> US National Institutes of Health, RePORTER application 10167682, DSPP Function, Pathophysiology, and Genetic Diagnosis (5R01DE027675-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167682. Licensed CC0.

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