As a transcription factor, the gene product of NFE2L2, the nuclear factor-erythroid 2-related factor 2 (NRF2), regulates the expression of a large number of genes including specifically various genes that are critical for defending the cell against insults as for example oxidative stress. International researchers led by Jutta Gärtner and Peter Huppke of the Children’s Hospital at the University Medical Center Göttingen have now linked de novo mutations in NFE2L2 to an early-onset multisystem disorder. Using whole-exome sequencing, they identified specific missense mutations in NFE2L2 as the genetic cause in four patients with a novel phenotype characterized by failure to thrive, immunodeficiency and neurologic symptoms. Interestingly, all four mutations have previously been reported as somatic mutations associated with various types of cancer.

Under non-stressed conditions, NRF2 is degraded rapidly within the cell to avoid “unnecessary” transcription of genes. Under stressed conditions, however, the protein remains stable and activates various cytoprotective genes. The mutations identified in this study led to accumulation of NRF2 even in the absence of stress, thereby mediating the expression of stress-response genes. In functional analyses, the researchers demonstrated also alterations in cytosolic redox balance. Biochemically, the patients with this novel phenotype present with hypohomocysteinemia, which might provide a basis for future options of presymptomatic diagnosis and early therapeutic intervention.

The results of the study have been published in Nature Communications.