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Resource and Technical AdvanceIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/jci.insight.197028

A dual-reporter mouse for therapeutic discovery in Angelman syndrome

Hanna Vihma,1 Lucas M. James,1 Hannah C. Nourie,1 Audrey L. Smith,1 Siyuan Liang,1 Carlee A. Friar,1 Tasmai Vulli,1 Lei Xing,1 Dale O. Cowley,2 Alain C. Burette,1 and Benjamin D. Philpot1

1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Burette, A. in: PubMed | Google Scholar

1Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2Animal Models Core, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Philpot, B. in: PubMed | Google Scholar |

Published February 3, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.197028.
Copyright © 2026, Vihma et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 3, 2026 - Version history
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Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternal UBE3A allele, the sole source of UBE3A in mature neurons due to epigenetic silencing of the paternal allele. Although emerging therapies are being developed to restore UBE3A expression by activating the dormant paternal UBE3A allele, existing mouse models for such preclinical studies have limited throughput and utility, creating bottlenecks for both in vitro therapeutic screening and in vivo characterization. To address this, we developed the Ube3a-INSG dual-reporter knock-in mouse, in which an IRES-Nanoluciferase-T2A-Sun1-sfGFP (INSG) cassette was inserted downstream of the endogenous Ube3a stop codon. The INSG model preserves UBE3A protein levels and function while enabling two complementary allele-specific readouts: Sun1-sfGFP and Nanoluciferase. We show that Sun1-sfGFP, a nuclear envelope-localized reporter, enables single-cell fluorescence analysis, whole-brain light-sheet imaging, and nuclear quantification by flow cytometry. Further, Nanoluciferase supports high-throughput luminescence assays for sensitive pharmacological profiling in cultured neurons and non-invasive in vivo bioluminescence imaging for pharmacodynamic assessment. By combining scalable screening, cellular analysis, and real-time in vivo monitoring in a single model, the Ube3a-INSG dual-reporter mouse provides a powerful platform to accelerate therapeutic development centered on UBE3A.

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