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

Huppke, Peter; Weissbach, Susann; Church, Joseph A.; Schnur, Rhonda E.; 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

doi:10.1038/s41467-017-00932-7

Cited by 72 publications

(62 citation statements)

References 49 publications

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“…Specifically, isoflavones are a type of naturally occurring isoflavonoids, which act as phytoestrogens in mammals, their targets were mainly distributed in module 1, 2, and 5 ( Supplementary Figure 6 ). Previous researches indicated that BRCA1 in module 1 was associated with risk of estrogen-receptor-negative breast cancer ( Milne et al, 2017 ), NFE2L2 in module 3 was related with cell multisystem disorder ( Huppke et al, 2017 ), and TP53 in module 5 was related with human immunodeficiency virus-related head and neck squamous cell carcinoma ( Gleber-Netto et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Exploring the Mechanism of Flavonoids Through Systematic Bioinformatics Analysis

Qiu

Lin-de

et al. 2018

Front. Pharmacol.

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Flavonoids are the largest class of plant polyphenols, with common structure of diphenylpropanes, consisting of two aromatic rings linked through three carbons and are abundant in both daily diets and medicinal plants. Fueled by the recognition of consuming flavonoids to get better health, researchers became interested in deciphering how flavonoids alter the functions of human body. Here, systematic studies were performed on 679 flavonoid compounds and 481 corresponding targets through bioinformatics analysis. Multiple human diseases related pathways including cancers, neuro-disease, diabetes, and infectious diseases were significantly regulated by flavonoids. Specific functions of each flavonoid subclass were further analyzed in both target and pathway level. Flavones and isoflavones were significantly enriched in multi-cancer related pathways, flavan-3-ols were found focusing on cellular processing and lymphocyte regulation, flavones preferred to act on cardiovascular related activities and isoflavones were closely related with cell multisystem disorders. Relationship between chemical constitution fragment and biological effects indicated that different side chain could significantly affect the biological functions of flavonoids subclasses. Results will highlight the common and preference functions of flavonoids and their subclasses, which concerning their pharmacological and biological properties.

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Section: Resultsmentioning

confidence: 99%

Exploring the Mechanism of Flavonoids Through Systematic Bioinformatics Analysis

Qiu

Lin-de

et al. 2018

Front. Pharmacol.

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“…Hence, upregulation of NRF2 in aging may improve cell function and stress resistance, which may in turn increase longevity. However, as NRF2 hyperactivity has been associated with cancer susceptibility and poor prognosis [35] , and activating inborn de novo mutations in NRF2 gene cause an early onset multisystem disorder [36] , it is important to understand the natural regulation of NRF2 function in aging for rational design of NRF2 targeted therapies against age-related disorders.…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells

et al. 2018

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Oxidative stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive stress responses to oxidative stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and electrophilic stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence.

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“…Of note, de novo mutations in human NRF2 gene that induce NRF2 were recently identified (Huppke et al., ), and the cases with the NRF2 induction displayed mild developmental delay, short stature and delayed bone age (Huppke et al., ). The phenotypes observed in the cases are consistent with the phenotype we have observed in the NEKO mice, including the small body length and low bone density.…”

Section: Discussionmentioning

confidence: 99%

Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo

et al. 2018

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Keap1 is a negative regulator of Nrf2, a master transcription factor that regulates cytoprotection against oxidative and electrophilic stresses. Although several studies have suggested that the Keap1-Nrf2 system contributes to bone formation besides the maintenance of redox homeostasis, how Nrf2 hyperactivation by Keap1 deficiency affects the bone formation remains to be explored, as the Keap1-null mice are juvenile lethal. To overcome this problem, we used viable Keap1-deficient mice that we have generated by deleting the esophageal Nrf2 in Keap1-null mice (NEKO mice). We found that the NEKO mice exhibit small body size and low bone density. Although nephrogenic diabetes insipidus has been observed in both the NEKO mice and renal-specific Keap1-deficient mice, the skeletal phenotypes are not recapitulated in the renal-specific Keap1-deficient mice, suggesting that the skeletal phenotype by Nrf2 hyperactivation is not related to the renal phenotype. Experiments with primary culture cells derived from Keap1-null mice showed that differentiation of both osteoclasts and osteoblasts was attenuated, showing that impaired differentiation of osteoblasts rather than osteoclasts is responsible for bone hypoplasia caused by Nrf2 hyperactivation. Thus, we propose that the appropriate control of Nrf2 activity by Keap1 is essential for maintaining bone homeostasis.

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

Cited by 72 publications

References 49 publications

Exploring the Mechanism of Flavonoids Through Systematic Bioinformatics Analysis

Exploring the Mechanism of Flavonoids Through Systematic Bioinformatics Analysis

MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells

Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo

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