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

Area of Science:

• Genetics
• Cellular Biology
• Human Disease

Background:

• The transcription factor NRF2 (encoded by NFE2L2) is a key regulator of cellular stress response in mammals.
• Somatic mutations in NFE2L2 that increase NRF2 activity are frequently observed in cancer, enhancing cell survival and drug resistance.

Purpose of the Study:

• To investigate the role of NFE2L2 mutations in a human genetic disorder.
• To characterize the clinical presentation and molecular consequences of NRF2 pathway dysregulation in a novel inherited disorder.

Main Methods:

• Clinical evaluation of four patients with de novo NFE2L2 mutations.
• Analysis of gene expression and cellular redox balance in affected individuals.
• Review of literature on NRF2 function in cancer and cellular defense.

Main Results:

• Identified de novo NFE2L2 mutations causing NRF2 accumulation in patients with early-onset multisystem disorder.
• Observed failure to thrive, immunodeficiency, and neurological symptoms in affected individuals.
• Detected widespread gene expression misregulation and altered cytosolic redox balance due to NRF2 accumulation.

Conclusions:

• Activating NFE2L2 mutations cause a novel inherited disorder distinct from cancer-associated mutations.
• NRF2 accumulation leads to significant cellular dysfunction and a complex clinical phenotype.
• Specific biomarkers including white matter lesions, hypohomocysteinaemia, and elevated G-6-P-dehydrogenase activity aid in diagnosis and suggest therapeutic targets.