Wilson Disease: Update on Pathophysiology and Treatment

Dev, Som; Kruse, Robert L.; Hamilton, James P.; Lutsenko, Svetlana

doi:10.3389/fcell.2022.871877

Cited by 40 publications

(36 citation statements)

References 69 publications

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“…Since SORL1, ATP7B, SETX , and FOXP1 genes have been previously linked to mitochondrial dysfunction [ 41 , 42 , 43 , 44 ], we performed mitochondrial staining in the patient’s fibroblasts with Hsp60, a mitochondrial chaperonin essential for protein folding and assembly in the mitochondrial matrix [ 33 ]. We observed a particular network shape in the patient with significantly altered mitochondrial parameters compared to neurologically healthy controls ( Figure 3 A–C).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, we provide evidence of an altered mitochondrial network in the patient (less branched mitochondria with decreased connectivity) compared to control individuals. As mentioned before, all four genes, ATP7B, SETX, SORL1 , and FOXP1 , have been associated with mitochondrial dysfunction [ 41 , 42 , 43 , 44 ], a common hallmark of many neurodegenerative conditions including PD and FTLD. Thus, we can hypothesize that the interaction among the four genes may contribute to altered mitochondria architecture in the patient.…”

Section: Discussionmentioning

confidence: 99%

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A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

Gawęda-Walerych

Sitek

Borczyk

et al. 2022

Genes

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Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient’s fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient’s fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson’s disease, and early onset Parkinson’s disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

Gawęda-Walerych

Sitek

Borczyk

et al. 2022

Genes

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“…Xiao and colleagues confirmed a crucial connection between copper homeostasis and hormone biosynthesis, demonstrating that the alteration of copper homeostasis achieved by a genetic mutation of the Cu exporter ATP7A produces a reduction in norepinephrine synthesis and a dysregulation of rest–activity cycles and arousal [ 33 ]. Mutations in ATP7B gene give rise to Wilson’s disease, in which defects in the ATP7B-mediated biliary copper excretion cause hepatic and systemic copper overload [ 34 ]. Necrosis of hepatocytes releases excess copper into the circulation and creates copper overload in other organs.…”

Section: Systemic and Cellular Copper Homeostasismentioning

confidence: 99%

Copper-Dependent Kinases and Their Role in Cancer Inception, Progression and Metastasis

2022

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In recent years, copper function has been expanded beyond its consolidated role as a cofactor of enzyme catalysis. Recent papers have demonstrated a new dynamic role for copper in the regulation of cell signaling pathways through direct interaction with protein kinases, modulating their activity. The activation of these pathways is exacerbated in cancer cells to sustain the different steps of tumor growth and dissemination. This review will focus on a novel proposed role for the transition metal copper as a regulator of cell signaling pathways through direct interaction with known protein kinases, which exhibit binding domains for this metal. Activation of these pathways in cancer cells supports both tumor growth and dissemination. In addition to the description of the results recently reported in the literature on the subject, relevance will be given to the possibility of controlling the cellular levels of copper and its homeostatic regulators. Overall, these findings may be of central relevance in order to propose copper and its homeostatic regulators as possible targets for novel therapies, which may act synergistically to those already existing to control cancer growth and dissemination.

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“…Wilson disease (WD) is another disorder of Cu homeostasis caused by mutations in the Cu-transporter ATP7B [4,5]. WD patients can present with tremor, ataxia, dysphagia [6][7][8], disrupted serotonin, dopamine (DA), norepinephrine (NE) metabolism, depression, and behavioral changes [7,9].…”

Section: Introductionmentioning

confidence: 99%

Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

Washington-Hughes

Roy²,

Seneviratne³

et al. 2023

PLoS Genet

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Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl’ cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.

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Wilson Disease: Update on Pathophysiology and Treatment

Cited by 40 publications

References 69 publications

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

Copper-Dependent Kinases and Their Role in Cancer Inception, Progression and Metastasis

Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

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