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

被引：60

作者：

Huppke, Peter ^{[1
,2
]}

Weissbach, Susann ^{[1
]}

Church, Joseph A. ^{[3
,4
]}

Schnur, Rhonda ^{[5
]}

Krusen, Martina ^{[6
]}

Dreha-Kulaczewski, Steffi ^{[1
]}

Kuehn-Velten, W. Nikolaus ^{[7
]}

Wolf, Annika ^{[1
]}

Huppke, Brenda ^{[1
]}

Millan, Francisca ^{[8
]}

Begtrup, Amber ^{[8
]}

Almusafri, Fatima ^{[9
]}

Thiele, Holger ^{[10
]}

Altmueller, Janine ^{[10
,11
]}

Nuernberg, Peter ^{[10
,12
,13
]}

Mueller, Michael ^{[2
,14
]}

Gaertner, Jutta ^{[1
]}

机构：

[1] Univ Med Ctr Gottingen, Div Pediat Neurol, Dept Pediat & Adolescent Med, D-37075 Gottingen, Germany

[2] Ctr Nanoscale Microscopy & Mol Physiol Brain CNMP, D-37075 Gottingen, Germany

[3] Univ Southern Calif, Childrens Hosp Los Angeles, Div Clin Immunol & Allergy, Los Angeles, CA 90027 USA

[4] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90027 USA

[5] Rowan Univ 3, Cooper Univ Hlth Care, Cooper Med Sch, Div Genet, Camden, NJ 08103 USA

[6] Lebenszentrum Konigsborn Fachklin Kinderneurol &, D-59425 Unna, Germany

[7] Med Lab Bremen, D-28357 Bremen, Germany

[8] GeneDx, Gaithersburg, MD 20877 USA

[9] Hamad Med Corp, Dept Pediat Clin & Metab Genet, Doha 3050, Qatar

[10] Univ Cologne, CCG, D-50931 Cologne, Germany

[11] Univ Klin Koln, Inst Human Genet, D-50931 Cologne, Germany

[12] Univ Cologne, CMMC, D-50931 Cologne, Germany

[13] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[14] Georg August Univ Gottingen, Univ Med, Inst Neuro & Sinnesphysiol, Zentrum Physiol & Pathophysiol, D-37075 Gottingen, Germany

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

SIGNALING PATHWAY; GENE-EXPRESSION; KEAP1; RECOGNITION; MICE; ELECTROPHILES; LANDSCAPE; CARCINOMA; DOMAIN; CELLS;

D O I：

10.1038/s41467-017-00932-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：10

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