Abstract: SA-PO0490
Disturbed IFNγ-STAT1 Signaling Explains Hypomagnesemia and Immune Deficiency in Kenny-Caffey Syndrome
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- De Baaij, Jeroen H.F., Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Bruno, Mariolina, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- van der Made, Caspar, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Schigt, Heidi, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Ilenwabor, Barnabas P, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Rother, Nils, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Latta, Femke, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Bos, Caro, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Feng, Wenguang, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States
- Ying, Wei-zhong, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States
- van de Veerdonk, Frank, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Duivenvoorden, Raphael, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
- Sanders, Paul W., University of Alabama at Birmingham Health System, Birmingham, Alabama, United States
- Hoenderop, Joost, Radboud universitair medisch centrum, Nijmegen, GE, Netherlands
Background
Kenny-Caffey syndrome type 2 (KCS2) is a rare hereditary disorder caused by mutations in FAM111A and comprises a complex phenotype including hypomagnesemia, bone abnormalities and recurrent infections. To date, the molecular mechanisms explaining the mineral disturbances and infections in KCS2 have not been resolved. To understand the renal magnesium wasting in patients with KCS2, we investigated the role of FAM111A in the kidney.
Methods
The transcriptional effects of IFNγ-STAT1-FAM111A signaling on the magnesium channel TRPM6 were assessed using luciferase assays and RNA expression analysis. Furthermore, urinary and serum magnesium levels were examined in STAT1 knockout (KO) mice and wild-type (WT) controls in response to IFNγ injections. Similarly, urinary magnesium excretion was assessed in immunodeficient patients receiving IFNγ treatment. Stimulation experiments were performed in cells isolated from patients with KCS2.
Results
Knockdown of Fam111a in mpkDCT cells led to the upregulation of antiviral genes, including STAT1, a key mediator of IFNγ signaling. Affinity-purification demonstrated that FAM111A directly interacts with STAT1. Pathogenic FAM111A variants decreased STAT1 phosphorylation upon IFNγ treatment in a protease-dependent manner. Indeed, patients with KCS2 showed significantly lower innate cytokine production upon stimulation, with elevated IFNγ levels.
To study the role of IFNγ signaling in magnesium homeostasis, patients with immunodeficiencies were treated with IFNγ resulting in reduced urinary magnesium excretion. The role of IFNγ-STAT1 signaling in magnesium homeostasis was confirmed in STAT1 KO mice, which displayed increased urinary magnesium wasting and an impaired response to IFNγ. Notably, TRPM6 was identified as a key target of IFNγ-induced STAT1 activity in renal tissues.
Conclusion
In conclusion, IFNγ–STAT1 signaling regulates renal magnesium reabsorption. Our results suggest that IFNγ controls renal magnesium reabsorption to maintain plasma magnesium concentrations during immune activation. In KCS2, FAM111A mutations lead to reduced STAT1 activity, resulting in mineral deficiencies, bone disturbances and dysregulated adaptive immunity.
Funding
- Government Support – Non-U.S.