# Exploration of Novel Strategies to Preserve Desmoplakin Variant Function

> **NIH NIH R15** · JAMES MADISON UNIVERSITY · 2024 · $25,290

## Abstract

Project Summary
 The desmosome is a proteinaceous cell-cell adherence structure that is only
found in tissues that undergo significant mechanical stress. One of its main functions is
to connect the intermediate filament latticework of adjacent cells. Desmoplakin (DSP) is
one of the central structural proteins within the desmosome. At least 80% of
Arrhythmogenic Cardiomyopathy (AC) cases are linked to variants in genes that encode
desmosomal proteins and about 5-15% of AC cases are specifically linked to variants in
the gene encoding desmoplakin (dsp). dsp variants are also strongly linked to Skin
Fragility Wooly Hair Syndrome (SFWHS) and Dilated Cardiomyopathy with Wooly Hair
and Keratoderma (DCWHK), two rare diseases characterized by fragile skin or fragile
skin plus cardiomyopathy. Our labs (PI Wright and co-PI Borzok) have previously
worked together to identify and characterize a novel molecular mechanism of
pathogenicity common to all three of these diseases. Namely, we found that a subset of
dsp variants result in the exposure of a usually occluded calpain cleavage site in DSP,
rendering the variant hypersensitive to proteolysis. This results in a loss of cellular DSP
levels, creates nonfunctioning desmosomes, and manifests clinically in weakened tissue
stability. We also previously discovered multiple strategies that can reverse this calpain
hypersensitivity: the introduction of secondary mutations that overlay the calpain
cleavage site, incubation of DSP with antibodies that occlude the calpain cleavage site,
and incubation of DSP with small molecules that block access to the calpain cleavage
site.
 While we have data showing that these strategies to manipulate DSP
degradation are effective, the molecular underpinnings of the strategies have not yet
been thoroughly analyzed. Here, we propose to examine the molecular mechanism of
how these strategies work on the protein level (aim 1). We will also test whether these
strategies are functional within the context of a cell (aim 2). These two aims will define
the parameters of how we can use pharmacological methods to correct a cell adhesive
deficiency.

## Key facts

- **NIH application ID:** 11034862
- **Project number:** 3R15GM148890-01S2
- **Recipient organization:** JAMES MADISON UNIVERSITY
- **Principal Investigator:** Nathan Thompson Wright
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $25,290
- **Award type:** 3
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11034862

## Citation

> US National Institutes of Health, RePORTER application 11034862, Exploration of Novel Strategies to Preserve Desmoplakin Variant Function (3R15GM148890-01S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11034862. Licensed CC0.

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