Huppke Peter, Weissbach Susann, Church Joseph A, Schnur Rhonda, Krusen Martina, Dreha-Kulaczewski Steffi, Kühn-Velten W Nikolaus, Wolf Annika, Huppke Brenda, Millan Francisca, Begtrup Amber, Almusafri Fatima, Thiele Holger, Altmüller Janine, Nürnberg Peter, Müller Michael, Gärtner Jutta
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075, Göttingen, Germany.
Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany.
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.
由NFE2L2编码的转录因子NRF2是哺乳动物细胞应激防御的主要调节因子。导致NRF2积累的NFE2L2体细胞突变促进癌细胞的存活和耐药性。在此我们表明，与新生突变相同的突变会导致一种早发性多系统疾病，出现生长发育迟缓、免疫缺陷和神经症状。NRF2积累导致基因表达广泛失调和胞质氧化还原平衡失衡。白质病变、低同型半胱氨酸血症和G-6-P-脱氢酶活性增加的独特组合将有助于对这种新型疾病进行早期诊断和治疗干预。NRF2转录因子调节哺乳动物细胞对压力的反应。在此，作者表明，在癌细胞中常见的NRF2激活突变在四名患有以免疫缺陷和神经症状为特征的多系统疾病的患者中被发现。
