Wilson Disease at a Single Cell Level

Ralle, Martina; Hüster, Dominik; Vogt, Stefan; Schirrmeister, W; Burkhead, Jason L.; Capps, Tony R.; Gray, Lawrence; Lai, Barry; Maryon, Edward B.; Lutsenko, Svetlana

doi:10.1074/jbc.m110.114447

Cited by 97 publications

(55 citation statements)

References 25 publications

(19 reference statements)

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“…In spite of that there are genetic mechanisms that control copper metabolism and homeostasis, related to copper absorption in many of the mammalian tissues, namely in the enterocyte, controlled by Ctr1 (a plasma membrane copper transport protein) [19]. It seems that copper transporter Ctr1 is downregulated when Cu is overloaded in the hepatocytes in WD [20]. If so, the downregulation of Ctr1 expression could lead to an augmentation of intestinal Cu content and inflammatory exacerbation, but a relationship between this transporter and inflammatory bowel disease has not yet been described.…”

Section: Discussionmentioning

confidence: 99%

Wilson’s Disease and Ulcerative Colitis in the Same Patient: Just A Coincidence? A Case Report and Literature Review

Nery¹

2011

Gastroenterol Res

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Ulcerative Colitis (UC) is a chronic relapsing inflammatory bowel disease (IBD). Wilson’s disease (WD) is a disorder of copper (Cu) metabolism due to inherited mutations in a gene encoding a putative Cu-transporting P-type ATPase, with a heterogeneous clinical presentation that includes hepatic, neurological, or psychiatric symptoms. The case of a 17-year-old female that presented with severe liver failure, three years after UC onset, and in which diagnosis of WD was established is reported. We review the literature and discuss the possible association between the two rare diseases. Although evidence of a common genetic background between UC and WD has not been described, high Cu serum level is present in both diseases. Cu is one of the trace elements necessary for antioxidant defenses during inflammatory processes, affecting the production of free radicals of oxygen and the levels of cellular antioxidants. The presence of both entities in the same patient may suggest abnormal metabolism of Cu or be just a coincidence.

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Section: Discussionmentioning

confidence: 99%

Wilson’s Disease and Ulcerative Colitis in the Same Patient: Just A Coincidence? A Case Report and Literature Review

Nery¹

2011

Gastroenterol Res

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“…Temporal and spatial distribution of Cu in hepatocytes may play an important role in Wilson’s disease pathology. Using high resolution synchrotron-based x-ray fluorescence imaging in situ, Ralle et al (2010) have shown that Cu does not continuously accumulate in ATP7B(−/−) hepatocytes. The lack of further accumulation is associated with the loss of Cu transporter CTR1 from the plasma membrane and the appearance of Cu-loaded lymphocytes and extracellular Cu deposits.…”

Section: Cu Toxicitymentioning

confidence: 99%

Copper: toxicological relevance and mechanisms

2014

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Copper (Cu) is a vital mineral essential for many biological processes. The vast majority of all Cu in healthy humans is associated with enzyme prosthetic groups or bound to proteins. Cu homeostasis is tightly regulated through a complex system of Cu transporters and chaperone proteins. Excess or toxicity of Cu, which is associated with the pathogenesis of hepatic disorder, neurodegenerative changes and other disease conditions, can occur when Cu homeostasis is disrupted. The capacity to initiate oxidative damage is most commonly attributed to Cu-induced cellular toxicity. Recently, altered cellular events, including lipid metabolism, gene expression, alpha-synuclein aggregation, activation of acidic sphingomyelinase and release of ceramide, and temporal and spatial distribution of Cu in hepatocytes, as well as Cu-protein interaction in the nerve system, have been suggested to play a role in Cu toxicity. However, whether these changes are independent of, or secondary to, an altered cellular redox state of Cu remain to be elucidated.

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“…108 One possible reason for this inconsistency is the abnormal distribution of copper in hepatocytes in animal models of WD. 109 It is also not clear to what degree the human WD phenotype is influenced by reduced protein levels and copper inhibition of ACHY. Betaine supplementation increases SAM and Dnmt3b levels and restores DNA methylation in the liver.…”

Section: Evidence Of Epigenetic Regulation In Wilson Diseasementioning

confidence: 99%

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

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Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.

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Wilson Disease at a Single Cell Level

Cited by 97 publications

References 25 publications

Wilson’s Disease and Ulcerative Colitis in the Same Patient: Just A Coincidence? A Case Report and Literature Review

Wilson’s Disease and Ulcerative Colitis in the Same Patient: Just A Coincidence? A Case Report and Literature Review

Copper: toxicological relevance and mechanisms

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

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