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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Binding Sites / genetics
  • Brain / diagnostic imaging*
  • Child
  • Developmental Disabilities / genetics*
  • Failure to Thrive / genetics*
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Infant
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Learning Disabilities / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Mutation, Missense
  • NF-E2-Related Factor 2 / genetics*
  • Syndrome


  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human

Supplementary concepts

  • Immune Deficiency Disease