# A novel genetic mutation reveals the molecular and cellular mechanisms of severe recurrent skin inflammation

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $34,250

## Abstract

PROJECT ABSTRACT
Inborn errors of immunity (IEI) are genetic disorders caused by monogenic germline mutations and have broad
clinical manifestations. Here, we present two patients affected by pyoderma gangrenosum (PG), an extremely
rare and severe neutrophilic necrotic skin disorder, without severe systemic autoinflammatory symptoms. Whole
exome sequencing (WES) revealed a homozygous R57C OTULIN missense mutation in each patient. OTULIN
encodes a deubiquitinase that is the only known enzyme that specifically cleaves linear ubiquitin chains that
have been added to target proteins by the linear ubiquitin chain assembly complex (LUBAC). The balance
between removal and addition of ubiquitin is crucial for immune homeostasis and responses to infection.
Previously reported germline OTULIN mutations affect this protein’s catalytic domain and cause a severe
systemic autoinflammatory largely driven by overactivation of NF-B signaling called OTULIN-related
autoinflammatory syndrome (ORAS). Here, we define a new monogenic disease caused by mutations in a
different domain of OTULIN and causing a distinct clinical phenotype. We have demonstrated that the R57C
mutation prevents OTULIN from binding to the LUBAC component HOIP but the ability to downregulate NF-B
activity remains intact suggesting a context-specific function of OTULIN. These patients’ unique phenotype
suggests that a previously unrecognized function for OTULIN in the skin. The overall hypothesis of this proposal
is that OTULIN’s function in keratinocytes differs from that in other cellular contexts, and this novel
mutation leads to development of pyoderma gangrenosum in patients. We will use computational method
and cutting-edge in vitro and ex vivo approaches to identify the roles of post-translational modification in
regulating OTULIN-dependent immune signaling. This discovery adds to the emerging spectrum of human
diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies for
maintaining immune homeostasis.

## Key facts

- **NIH application ID:** 10895288
- **Project number:** 5F31AR082264-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Hwi (Deborah) M Gil
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,250
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895288

## Citation

> US National Institutes of Health, RePORTER application 10895288, A novel genetic mutation reveals the molecular and cellular mechanisms of severe recurrent skin inflammation (5F31AR082264-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10895288. Licensed CC0.

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