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

Author

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  • Peter Huppke

    (Division of Pediatric Neurology, University Medical Center Göttingen
    Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB))

  • Susann Weissbach

    (Division of Pediatric Neurology, University Medical Center Göttingen)

  • Joseph A. Church

    (Divison of Clinical Immunology and Allergy, Childrens Hospital Los Angeles, and Keck School of Medicine University of Southern California)

  • Rhonda Schnur

    (Division of Genetics, Cooper University Health Care, Cooper Medical School of Rowan University 3)

  • Martina Krusen

    (Lebenszentrum Königsborn Fachklinik für Kinderneurologie und Sozialpädiatrie mit Sozialpädiatrischem Zentrum)

  • Steffi Dreha-Kulaczewski

    (Division of Pediatric Neurology, University Medical Center Göttingen)

  • W. Nikolaus Kühn-Velten

    (Medical Laboratory Bremen)

  • Annika Wolf

    (Division of Pediatric Neurology, University Medical Center Göttingen)

  • Brenda Huppke

    (Division of Pediatric Neurology, University Medical Center Göttingen)

  • Francisca Millan

    (GeneDx)

  • Amber Begtrup

    (GeneDx)

  • Fatima Almusafri

    (Clinical and Metabolic Genetics, Hamad Medical Corporation)

  • Holger Thiele

    (Cologne Center for Genomics (CCG), University of Cologne)

  • Janine Altmüller

    (Cologne Center for Genomics (CCG), University of Cologne
    Institute of Human Genetics, Universitätsklinik Köln)

  • Peter Nürnberg

    (Cologne Center for Genomics (CCG), University of Cologne
    Center for Molecular Medicine Cologne (CMMC), University of Cologne
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne)

  • Michael Müller

    (Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)
    Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Universitätsmedizin)

  • Jutta Gärtner

    (Division of Pediatric Neurology, University Medical Center Göttingen)

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.

Suggested Citation

  • Peter Huppke & Susann Weissbach & Joseph A. Church & Rhonda Schnur & Martina Krusen & Steffi Dreha-Kulaczewski & W. Nikolaus Kühn-Velten & Annika Wolf & Brenda Huppke & Francisca Millan & Amber Begtru, 2017. "Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00932-7
    DOI: 10.1038/s41467-017-00932-7
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    Cited by:

    1. Irene Molina-Gonzalez & Rebecca K. Holloway & Zoeb Jiwaji & Owen Dando & Sarah A. Kent & Katie Emelianova & Amy F. Lloyd & Lindsey H. Forbes & Ayisha Mahmood & Thomas Skripuletz & Viktoria Gudi & Jame, 2023. "Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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