Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases.

Copper transporting P-type (P1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD-1, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD-1, MBD-2, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P1B-1-disorders and ongoing clinical trials.

Structure and mechanism of the human copper transporting ATPases: Fitting the pieces into a moving puzzle.

Human copper transporters ATP7B and ATP7A deliver copper to biosynthetic pathways and maintain copper homeostasis in the cell. These enzymes combine several challenges for structural biology because they are large low abundance membrane proteins with many highly mobile domains and long disordered loops. No method has yet succeeded in solving the structure of the complete fully functional protein. Still, X-ray crystallography, Cryo-EM and NMR helped to piece together a structure based model of the enzyme activity and regulation by copper. We review the structures of ATP7B and ATP7A with an emphasis on the mechanistic insights into the unique aspects of the transport function and regulation of the human copper ATPases that have emerged from more than twenty years of research.

Epidemiology of Wilson's Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions.

Wilson's disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient's condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000-45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed.

AP-1γ2 is an adaptor protein 1 variant required for endosome-to-Golgi trafficking of the mannose-6-P receptor (CI-MPR) and ATP7B copper transporter.

Selective retrograde transport from endosomes back to the trans-Golgi network (TGN) is important for maintaining protein homeostasis, recycling receptors, and returning molecules that were transported to the wrong compartments. Two important transmembrane proteins directed to this pathway are the Cation-Independent Mannose-6-phosphate receptor (CI-MPR) and the ATP7B copper transporter. Among CI-MPR functions is the delivery of acid hydrolases to lysosomes, while ATP7B facilitates the transport of cytosolic copper ions into organelles or the extracellular space. Precise subcellular localization of CI-MPR and ATP7B is essential for the proper functioning of these proteins. This study shows that both CI-MPR and ATP7B interact with a variant of the clathrin adaptor 1 (AP-1) complex that contains a specific isoform of the γ-adaptin subunit called γ2. Through synchronized anterograde trafficking and cell-surface uptake assays, we demonstrated that AP-1γ2 is dispensable for ATP7B and CI-MPR exit from the TGN while being critically required for ATP7B and CI-MPR retrieval from endosomes to the TGN. Moreover, AP-1γ2 depletion leads to the retention of endocytosed CI-MPR in endosomes enriched in retromer complex subunits. These data underscore the importance of AP-1γ2 as a key component in the sorting and trafficking machinery of CI-MPR and ATP7B, highlighting its essential role in the transport of proteins from endosomes.

Integrative analysis of the cuproptosis-related gene ATP7B in the prognosis and immune infiltration of IDH1 wild-type glioma.

Glioma is the most common malignant tumor in the brain and the central nervous system with a poor prognosis, and wild-type isocitrate dehydrogenase (IDH) glioma indicates a worse prognosis. Cuproptosis is a recently discovered form of cell death regulated by copper-dependent mitochondrial respiration. However, the effect of cuproptosis on tumor prognosis and immune infiltration is not clear. In this research, we analyzed of public databases to show the correlation between cuproptosis-related genes and the prognosis of IDH1 wild-type glioma. Nine out of 12 genes were upregulated in IDH1 wild-type glioma patients, and 6 genes were significantly associated with overall survival (OS), while 5 genes were associated with progression-free survival (PFS). Then, we constructed a prognostic cuproptosis-related gene signature for IDH1 wild-type glioma patients. ATP7B was considered an independent prognostic indicator, and a low expression level of ATP7B was related to a shorter period of OS and PFS. Moreover, downregulation of ATP7B was correlated not only with the infiltration of activated NK cells, CD8 + T cells and M2 macrophages; but also with high expression of immune checkpoint genes and tumor mutation burden (TMB). In the IDH1 wild-type glioma tissues we collected, our data also confirmed that high tumor grade was accompanied by low expression of ATP7B and high expression of PD-L1, which was associated with increasing infiltration of CD8 + immune cells. In conclusion, our research constructed a prognostic cuproptosis-related gene signature model to predict the prognosis of IDH1 wild-type glioma. ATP7B is deemed to be a potential prognostic indicator and novel immunotherapy biomarker for IDH1 wild-type glioma patients.

ATP7A-dependent copper sequestration contributes to termination of ß-CATENIN signaling during early adipogenesis.

OBJECTIVES: Adipocyte fate determination is tightly regulated by extrinsic signaling pathways and intrinsic metabolic and morphologic changes that maintain adipose tissue function. Copper (Cu) homeostasis is required for the normal metabolism of mature adipocytes, whereas the role of Cu in adipogenesis is unclear. METHODS: To determine the role of Cu is adipocytes differentiation, we used 3T3-L1 adipocytes, immunocytochemistry, X-ray fluorescence, mass-spectrometry, pharmacological treatments, and manipulations of copper levels. RESULTS: In differentiating 3T3-L1 cells, adipogenic stimuli trigger the upregulation and trafficking of the Cu transporter Atp7a, thus causing Cu redistribution from the cytosol to vesicles. Disrupting Cu homeostasis by the deletion of Atp7a results in Cu elevation and inhibition of adipogenesis. The upregulation of C/EBPß, an initial step of adipogenesis, is not affected in Atp7a-/- cells, whereas the subsequent upregulation of PPARγ is inhibited. Comparison of changes in the Atp7a-/- and wild type cells proteomes during early adipogenesis revealed stabilization of ß-catenin, a negative regulator of adipogenesis. Cu chelation, or overexpression of the Cu transporter ATP7B in Atp7a-/- cells, restored ß-catenin down-regulation and intracellular targeting. CONCLUSIONS: Cu buffering during early adipogenesis contributes to termination of ß-catenin signaling. Abnormal upregulation of ß-catenin was also observed in vivo in the livers of Atp7b-/- mice, which accumulate Cu, suggesting a tissue-independent crosstalk between Cu homeostasis and the Wnt/ß-catenin pathway. These results point to a new regulatory role of Cu in adipocytes and contribute to better understanding of human disorders of Cu misbalance.

Teaching NeuroImage: Neuroimaging Features of Wilson Disease.

A 13-year-old boy of nonconsanguineous parents presented with abnormal body movements, gait difficulty, and slurring of speech for 2 years. On examination, he had rigidity, dystonia, dysarthria, and drooling. Ophthalmologic examination revealed bilateral Kayser-Fleischer rings. He had elevated serum "free" copper levels (41.2 µg/dL [range:10-15]), 24-hour urine copper levels (895.7 µg/d [range:<60]), and reduced serum ceruloplasmin levels (4.3 mg/dL (range:20-40]). MRI revealed "face of giant panda" appearance (Figure A), T2-fluid attenuated inversion recovery hyperintensities (Figure, B and C), and frontal cystic encephalomalacic changes (Figure D), suggestive of Wilson disease (WD). Face of giant panda in WD, first described by Hitoshi et al.,1 is due to high signal intensity in tegmentum with normal signals in red nuclei forming the eyes, normal signals of pars reticulata (lateral portion) of substantia nigra forming the ears, and hypointensity of superior colliculus forming the chin.2 Bilateral cystic changes are less commonly reported in WD.3 Recognizing diverse neuroimaging signatures beyond well-known findings in WD enhances diagnostic accuracy.

A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.

Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD.

Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B.

The homologous P-type copper-ATPases (Cu-ATPases) ATP7A and ATP7B are the key regulators of copper homeostasis in mammalian cells. In polarized epithelia, upon copper treatment, ATP7A and ATP7B traffic from the trans-Golgi network (TGN) to basolateral and apical membranes, respectively. We characterized the sorting pathways of Cu-ATPases between TGN and the plasma membrane and identified the machinery involved. ATP7A and ATP7B reside on distinct domains of TGN in limiting copper conditions, and in high copper, ATP7A traffics to basolateral membrane, whereas ATP7B traverses common recycling, apical sorting and apical recycling endosomes en route to apical membrane. Mass spectrometry identified regulatory partners of ATP7A and ATP7B that include the adaptor protein-1 complex. Upon knocking out pan-AP-1, sorting of both Cu-ATPases is disrupted. ATP7A loses its trafficking polarity and localizes on both apical and basolateral surfaces in high copper. By contrast, ATP7B loses TGN retention but retained its trafficking polarity to the apical domain, which became copper independent. Using isoform-specific knockouts, we found that the AP-1A complex provides directionality and TGN retention for both Cu-ATPases, whereas the AP-1B complex governs copper-independent trafficking of ATP7B solely. Trafficking phenotypes of Wilson disease-causing ATP7B mutants that disrupts putative ATP7B-AP1 interaction further substantiates the role of AP-1 in apical sorting of ATP7B.

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype.

Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.

The interplay between copper metabolism and microbes: in perspective of host copper-dependent ATPases ATP7A/B.

Copper, a vital element in various physiological processes, is transported from the gastrointestinal tract to tissues and cells through diverse copper transporters. Among these transporters, ATP7A and ATP7B play significant roles in regulating systemic copper metabolism and exhibit precise regulation in their intracellular trafficking. These transporters undergo dynamic shuttling between the trans-Golgi network (TGN) and the plasma membrane via the endocytic recycling mechanism, which involves the retromer and other associated factors. Interestingly, the antimicrobial attribute of copper implies a potential connection between microbial infection and copper metabolism. Several microbes, including Salmonella enterica, Cryptococcus, Influenza A virus (IAV) and Zika virus (ZIKV) have been observed to impact the regulatory mechanisms of ATP7A/B, either directly or indirectly, as a means of survival. This review summarizes the key features and trafficking mechanisms of the copper transporters ATP7A/B, and examines the intricate interplay between microbes and copper metabolism. Ultimately, it highlights how microbes can perturb copper homeostasis through interactions with host factors, offering valuable insights into the mechanistic aspects of host-microbe interactions.

[Analysis of clinical characteristics and ATP7A gene variants in a Chinese pedigree affected with Menkes disease].

OBJECTIVE: To explore the clinical characteristics and variants of ATP7A gene in a child with Menkes disease. METHODS: A child with Menkes disease diagnosed at the West China Second Hospital of Sichuan University and its family members in March 2022 was selected as the study subjects. Clinical manifestations and results of laboratory tests and genetic testing were summarized. RESULTS: The main manifestations of the child included seizures, global development delay, facial dysmorphism, sparse and curly hair, increased lactate and pyruvate, and significantly decreased cuprin. EEG showed frequent issuance of multifocal spikes, spines, polyspines (slow) and polymorphic slow waves. Multiple tortuous vascular shadows were observed on cranial MRI. Whole exome sequencing revealed that the child has harbored a hemizygous c.3076delA (p.ile1026*) variant of the ATP7A gene, which was inherited from his mother. The variant may lead to premature termination of protein translation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PM2+PP4). CONCLUSION: The c.3076delA (p.Ile1026*) variant of the ATP7A gene probably underlay the Menkes disease in this child. Above finding has provided evidence for clinical diagnosis. The significantly increased lactic acid and pyruvate can be used as a reference for the diagnosis and management of Menkes disease. Microscopic abnormalities in the hair of the carriers may also facilitate their diagnosis.

Cuproptosis-related molecular patterns and gene (ATP7A) in hepatocellular carcinoma and their relationships with tumor immune microenvironment and clinical features.

BACKGROUND: Cuproptosis has been studied in various aspects as a new form of cell death. AIMS: We hope to explore the molecular patterns and genes related to cuproptosis in evaluating and predicting the prognosis of hepatocellular carcinoma (HCC), as well as the impact of tumor immune microenvironment. METHODS AND RESULTS: Sixteen cuproptosis related gene (CRGs) and cuproptosis related molecular and gene characteristics were comprehensively analyzed from 492 HCC samples. Cuproptosis related molecular patterns were generated by consensus clustering algorithm, including cuproptosis clusters, cuproptosis gene clusters (CGC) and cuproptosis score (CS). The characteristics of tumor microenvironment (TME) and tumor immune cells were described by the ssGSEA and ESTIMATE algorithms. Cuproptosis score was established to assess the clinical characteristics, prognostic and immunotherapy. The role and mechanism of CRG (ATP7A) in HCC, as well as its relationship with TME and immune checkpoints, have been further explored. The results of somatic mutation, copy number variations (CNV), and CRGs expression in HCC suggested the CRGs might participate in the HCC oncogenesis. The cuproptosis clusters were closely related to the clinical pathological characteristics, biological processes, and prognosis of HCC. The three CGC was revealed to be consistent with the three immune infiltration characterizations, including immune-high, immune-mid, and immune-low subtypes. Higher CS was characterized by decreased TMB, activated immunity, higher immune cell proportion score (IPS) and better overall survival (OS), which indicated higher CS was immune-high type and with better treatment effect and prognosis. The ATP7A had the highest hazard ratio (HR = 1.465, p < .001), was high expression in HCC tissues and with a shorter 5-year OS. Knocking down ATP7A could enhance intracellular copper concentration, cause a decrease in DLAT expression, and induce cuproptosis and inhibit cell proliferation and migration. ATP7A was also positively correlated with most cancer immune cells and immune checkpoints. CONCLUSION: Taken together, this research revealed the cuproptosis related molecular patterns and genes associated with the clinical pathological characteristics, TME phenotype and prognosis of HCC. The CS will further deepen our understanding of the TME characteristics of HCC, and the involvement of ATP7A in cuproptosis will provide new ideas for predicting HCC prognosis and immunotherapy.

Copper-independent lysosomal localisation of the Wilson disease protein ATP7B.

In hepatocytes, the Wilson disease protein ATP7B resides on the trans-Golgi network (TGN) and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in the endolysosomal compartment of hepatocytes but not in non-hepatic cells. These ATP7B-harbouring lysosomes lie in close proximity of ~10 nm to the TGN. ATP7B constitutively distributes itself between the sub-domain of the TGN with a lower pH and the TGN-proximal lysosomal compartments. The presence of ATP7B on TGN-lysosome colocalising sites upon Golgi disruption suggested a possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localisation of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper-replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN-proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper-independent lysosomal localisation of ATP7B and the importance of TGN-proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway.

Severe early-onset Wilson disease caused by a common pathogenic variant in the Bukharan Jewish population in Israel.

BACKGROUND: Wilson disease is caused by pathogenic variants in the ATP7B gene which encodes a copper-transporting ATPase. AIMS: Describe a common founder pathogenic variant among Bukharan Jews and to assess its prevalence, clinical features, and outcome. METHODS: The cohort consisted of patients of Bukharan Jewish descent diagnosed with Wilson disease at a tertiary pediatric medical center in 2013-2018. Clinical and genetic data were collected and analyzed. RESULTS: Six patients from 4 unrelated families who were homozygous for the c.3784G > T p.(Val1262Phe) pathogenic variant in ATP7B were identified. Five presented with elevated aminotransferase levels, and one, with acute liver failure. Mean age at diagnosis was 8.7 years (5-12.5). Serum ceruloplasmin level was extremely low in all patients (1.9-7 mg/dL; mean 3.2(. The variant was identified in a heterozygous state in 5/153 Bukharan Jews; 2/33 from our local exome database and 3/120 healthy unrelated Bukharan Jews in another cohort, for an estimated carrier frequency of ∼1:30. CONCLUSIONS: We report a common founder pathogenic variant in the ATP7B gene among Bukharan Jews associated with severe early-onset Wilson disease. Given the clinical severity, high frequency of the variant, and being a treatable disease, its inclusion in pre-symptomatic screening in the Bukharan Jewish community should be considered. Furthermore, WD should be part of future genetic newborn screening programs in Israel and worldwide, to enable early treatment and prevention of future life-threatening complications.

Copper-transporting ATPases throughout the animal evolution - From clinics to basal neuron-less animals.

Copper-transporting ATPases are a group of heavy metal-transporting proteins and which can be found in all living organisms. In animals, they are generally referred to as ATP7 proteins and are involved in many different physiological processes including the maintaining of copper homeostasis and the supply of copper to cuproenzymes. A single ATP7 gene is present in non-chordate animals while it is divided into ATP7A and ATP7B in chordates. In humans, dysfunction of ATP7 proteins can lead to severe genetic disorders, such as, Menkes disease and Wilson's disease, which are characterized by abnormal copper transport and accumulation, causing significant health complications. Therefore, there is a substantial amount of research on ATP7 genes and ATP7 proteins in humans and mice to understand pathophysiological conditions and find potential therapeutic interventions. Copper-transporting ATPases have also been investigated in some non-mammalian vertebrates, protostomes, single-cellular eukaryotes, prokaryotes, and archaea to gain useful evolutionary insights. However, ATP7 function in many animals has been somewhat neglected, particularly in non-bilaterians. Previous reviews on this topic only broadly summarized the available information on the function and evolution of ATP7 genes and ATP7 proteins and included only the classic vertebrate and invertebrate models. Given this, and the fact that a considerable amount of new information on this topic has been published in recent years, the present study was undertaken to provide an up-to-date, comprehensive summary of ATP7s/ATP7s and give new insights into their evolutionary relationships. Additionally, this work provides a framework for studying these genes and proteins in non-bilaterians. As early branching animals, they are important to understand the evolution of function of these proteins and their important role in copper homeostasis and neurotransmission.

Bioactive copper(II) agents and their potential involvement in the treatment of copper deficiency-related orphan diseases.

The deregulation of copper homoeostasis can promote various diseases such as Menkes disease or hypertrophic cardioencephalomyopathy. We have recently synthesized solid copper(II) complexes ([Cu(His)2Cl2] and [Cu(Ser)2]), stable in physiological media and with potential as therapeutic agents. This report describes: i) the biocompatibility of these complexes at concentrations up to 100 µM using a differentiated Caco-2 cells model; ii) their transport across the intestinal epithelium using a transepithelial resistance assay and monitoring the amount of copper complexes at the apical and basolateral sides of the cells. The results suggest that the flow occurs through paracellular routes. The intracellular copper retention was <2.7% with no significant differences in intracellular copper content between 6 h and 48 h, suggesting an early copper retention process. Furthermore, this is the first evidence that demonstrates [Cu(His)2Cl2] and [Cu(Ser)2] induce transcriptional downregulation of the four major copper transporters (CTR1, DMT1, ATP7A, ATP7B), and the upregulation of the metallothionein gene expression. A remarkable finding was the increase in cytochrome c oxidase activity observed after the treatment of differentiated Caco-2 cells with copper(II) complexes at concentrations of 50-100 µM. The understanding of the transport mechanisms of these copper(II) complexes across the intestinal epithelium and of their subsequent biological activities could contribute to the development of optimal pharmaceutical formulations for the therapy of copper deficiency-related diseases.

Regulation of Atp7a RNA contributes to differentiation-dependent Cu redistribution in skeletal muscle cells.

Cu (Cu) is essential for several biochemical pathways due to its role as a catalytic cofactor or allosteric regulator of enzymes. Its import and distribution are tightly controlled by transporters and metallochaperones and Cu homeostasis is maintained by balancing Cu uptake and export. Genetic diseases are caused by impaired Cu transporters CTR1, ATP7A, or ATP7B but little is known about the regulatory mechanisms by which these proteins meet the fluctuating demands of Cu in specific tissues. Cu is required for differentiation of skeletal myoblasts to myotubes. Here, we demonstrate that ATP7A is needed for myotube formation and that its increased abundance during differentiation is mediated by stabilization of Atp7a mRNA via the 3' untranslated region. Increased ATP7A levels during differentiation resulted in increased Cu delivery to lysyl oxidase, a secreted cuproenzyme that needed for myotube formation. These studies identify a previously unknown role for Cu in regulating muscle differentiation and have broad implications for understanding Cu-dependent differentiation in other tissues.

A Systematic Review and Meta-Analysis of the R778L Mutation in ATP7B With Wilson Disease in China.

BACKGROUND: Wilson disease (WD) is a hereditary disorder of copper metabolism, caused by mutations in the ATP7B gene. There are more than 1000 pathogenic variants identified in ATP7B. R778L is the most common ATP7B mutation in China. METHODS: To estimate whether R778L is associated with the onset age of WD and other clinical variables. Genotyping results of ATP7B gene were collected in our 22 patients with WD. We then conducted a systematic review and meta-analysis in databases, using the keywords Wilson disease and R778L mutation. RESULTS: After the screening, a total of 23 studies were included, including 3007 patients with WD. Patients with R778L mutation presented at an earlier age (standardized mean difference [SMD] = -0.18 [95% confidence interval, -0.28 to 0.08], P = 0.0004) and had lower ceruloplasmin concentration (SMD = -0.21 [95% confidence interval, -0.40 to -0.02], P = 0.03) than the patients without the R778L mutation. However, sex (odds ratio [OR] = 1.07 [95% confidence interval, 0.89 to 1.29], P = 0.32) and first presentation were not associated with R778L mutation in WD (hepatic: OR = 1.37 [95% confidence interval, 0.87 to 2.16, P = 0.17; neurological: OR = 0.79 [95% confidence interval, 0.48 to 1.30, P = 0.35; mix: OR = 1.04 [95% confidence interval, 0.42 to 2.53, P = 0.87; asymptomatic/others: OR = 1.98 [95% confidence interval, 0.49 to 7.96, P = 0.34). CONCLUSIONS: Our results indicated that the R778L mutation is associated with an earlier presentation and lower ceruloplasmin concentration in China.

[Factors influencing the clinical phenotype of hepatolenticular degeneration].

Hepatolenticular degeneration is an autosomal recessive genetic disease caused by mutations in the ATP7B gene. More than 800 mutations have been identified in the ATP7B gene so far, with significant differences in clinical phenotypes among different mutation sites. Totally different clinical phenotypic mutations can even exist in the same gene. Although copper accumulation due to gene mutation is the basis of the pathogenesis of hepatolenticular degeneration, more and more evidence demonstrates that it is difficult to explain the diversity of clinical manifestations solely from the perspective of gene mutation. Therefore, this article reviews the research progress on the factors influencing genotype, modifier genes, epigenetics, age, gender, diet, and other factors on the phenotype of patients with hepatolenticular degeneration.