# The impact of ITPR3 mutations on immunity

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $246,000

## Abstract

Project Summary
The inositol trisphosphate receptors (ITPR1, ITPR2, ITPR3) are present in the endoplasmic
reticulum, forming homo- or hetero- tetrameric complexes to control calcium release. Upon
binding to the second messenger, inositol 1,4,5 trisphosphate (IP3), the ITPR controlled release
of calcium controls differentiation, proliferation, and death processes for every cell type in the
body. We identified the same single allelic mutation in the Inositol Tris Phosphate Receptor Type
3 (ITPR3) in two unrelated children. The missense mutation creates a p.Arg2524Cys amino acid
substitution within the calcium channel. These children have immunodeficiency, Charcot-Marie
Tooth disease and partial to complete anhidrosis. While autosomal recessive ITPR3 mutations
cause one form of CMT syndrome, immune system problems and sweating defects are not
normally seen. In fact, most single allelic mutations in ITPR3 are benign due to compensatory
functions by ITPR1 and ITPR2. To understand the basis for the more widespread clinical
presentation our two patients with the single allelic p.R2524C variant, as well as an expanding
number being reported elsewhere, we genocopied the mutation in mice. Our preliminary findings
suggest this Itpr3 p.R2524C variant forms a cell-type specific dominant negative. In the current
proposal, we will determine the impact of this Itpr3 mutation on cell signaling in the immune,
neuronal, and eccrine systems. A characterization of the T and B cells of the adaptative immune
system will be done with a combination of functional assays and signaling studies. Additionally, a
characterization of the Schwann cells of the peripheral nervous system and eccrine cells will be
undertaken. The studies will be complemented with knockdown approaches using shRNA
technologies to determine if functionality can be restored by selectively targeting Itpr3.

## Key facts

- **NIH application ID:** 10888883
- **Project number:** 1R21AI176445-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** NICOLAI Stanislas Cyrille VAN OERS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $246,000
- **Award type:** 1
- **Project period:** 2024-06-21 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888883

## Citation

> US National Institutes of Health, RePORTER application 10888883, The impact of ITPR3 mutations on immunity (1R21AI176445-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10888883. Licensed CC0.

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