# A novel autoinflammatory skin disease in a patient with mutations in alpha-T-catenin

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2021 · $185,440

## Abstract

Abstract
Inborn errors of immunity comprise over 300 distinct disorders. Among these are an expanding number of
monogenic auto-inflammatory disorders, characterized by sterile inflammation systemically or in specific
organs. This proposal stems from the identification of a child who appears to have a novel autoinflammatory
disease characterized by inflammatory skin disease and associated with increased type I interferon production
but without recurrent fever. This patient has compound heterozygous mutations in the gene encoding αT-
catenin: CTNNA3. The α-catenins are actin-binding proteins that interact with cadherins to mediate cell-cell
adhesion and tissue organization. Different mutations in CTNNA3 are linked with a specific cardiac disease in
humans, arrhythmogenic right ventricular dysplasia, but this child does not have cardiac disease. Importantly,
there are no prior associations of mutations in CTNNA3 with inflammatory skin disease. Here we seek to
understand how this patient’s mutant αT-catenin drives skin inflammation and increased type I interferon
production. Our preliminary data demonstrate that αT-catenin is highly expressed in sebaceous glands in
healthy human skin. The skin serves as a barrier between an organism and the surrounding environment. Hair
follicles breach this anatomic barrier and provide a potential portal of entry for pathogens; they are thus a site
of much immunologic activity. Anatomically associated with hair follicles, sebaceous glands secrete lipids that
contribute to skin barrier function and serve as nutrients for commensal microbiota. Sebaceous glands also
produce antimicrobial peptides, cytokines, and chemokines to modulate skin immunity. Mice lacking
sebaceous glands develop a phenotype similar to this patient. The central hypothesis of this proposal is that
αT-catenin is critical for normal sebaceous gland function. Further, we propose that this patient’s CTNNA3
mutations disrupt αT-catenin function, altering sebaceous gland activity and culminating in inflammatory skin
disease. We will first determine how this patient’s CTNNA3 mutations affect the fundamental biology of αT-
catenin, its association with binding proteins, and its subcellular localization. Next we will characterize how the
mutant αT-catenin affects sebaceous gland structure and function, using a combination of patient skin biopsy
samples and cultured human sebaceous gland cells (sebocytes). Finally, we will test the hypothesis that the
increased type I interferon signature in this patient stems either from a direct effect on skin cells or indirectly
through effects of altered sebaceous gland activity on the skin flora. The proposed studies will allow us to
characterize a novel autoinflammatory skin disease and the first human disease associated with reduced
sebaceous gland function; they may also provide insight to improve treatment of this patient’s skin disease.
Additionally, we will gain new knowledge of how the skin and its appendages (...

## Key facts

- **NIH application ID:** 10197026
- **Project number:** 5R21AI149334-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Bryce Binstadt
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $185,440
- **Award type:** 5
- **Project period:** 2020-06-17 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197026

## Citation

> US National Institutes of Health, RePORTER application 10197026, A novel autoinflammatory skin disease in a patient with mutations in alpha-T-catenin (5R21AI149334-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197026. Licensed CC0.

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