Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder PMID: 29018201

GLP-1 and Obesity Research

2026-08-18

Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder

Nat Commun. 2017 Oct 10;8(1):818. doi: 10.1038/s41467-017-00932-7.

Peter Huppke ¹ ² , Susann Weissbach ³ , Joseph A Church ⁴ , Rhonda Schnur ⁵ , Martina Krusen ⁶ , Steffi Dreha-Kulaczewski ³ , W Nikolaus Kühn-Velten ⁷ , Annika Wolf ³ , Brenda Huppke ³ , Francisca Millan ⁸ , Amber Begtrup ⁸ , Fatima Almusafri ⁹ , Holger Thiele ¹⁰ , Janine Altmüller ¹⁰ ¹¹ , Peter Nürnberg ¹⁰ ¹² ¹³ , Michael Müller ¹⁴ ¹⁵ , Jutta Gärtner ³

Affiliations

1. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075, Göttingen, Germany. [email protected].
2. Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany. [email protected].
3. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075, Göttingen, Germany.
4. Divison of Clinical Immunology and Allergy, Childrens Hospital Los Angeles, and Keck School of Medicine University of Southern California, Los Angeles, CA, 90027, USA.
5. Division of Genetics, Cooper University Health Care, Cooper Medical School of Rowan University 3, Camden, NJ, 08103, USA.
6. Lebenszentrum Königsborn Fachklinik für Kinderneurologie und Sozialpädiatrie mit Sozialpädiatrischem Zentrum, 59425, Unna, Germany.
7. Medical Laboratory Bremen, 28357, Bremen, Germany.
8. GeneDx, Gaithersburg, MD, 20877, USA.
9. Department of Pediatrics, Clinical and Metabolic Genetics, Hamad Medical Corporation, 3050, Doha, Qatar.
10. Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931, Germany.
11. Institute of Human Genetics, Universitätsklinik Köln, 50931, Cologne, Germany.
12. Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
13. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
14. Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany.
15. Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Universitätsmedizin, 37075, Göttingen, Germany.

Abstract

Transcription factor NRF2, encoded by NFE2L2, is the master regulator of defense against stress in mammalian cells. Somatic mutations of NFE2L2 leading to NRF2 accumulation promote cell survival and drug resistance in Cancer cells. Here we show that the same mutations as inborn de novo mutations cause an early onset multisystem disorder with failure to thrive, immunodeficiency and neurological symptoms. NRF2 accumulation leads to widespread misregulation of gene expression and an imbalance in cytosolic redox balance. The unique combination of white matter lesions, hypohomocysteinaemia and increased G-6-P-dehydrogenase activity will facilitate early diagnosis and therapeutic intervention of this novel disorder.The NRF2 transcription factor regulates the response to stress in mammalian cells. Here, the authors show that activating mutations in NRF2, commonly found in Cancer cells, are found in four patients with a multisystem disorder characterized by immunodeficiency and neurological symptoms.