Impaired cellular copper regulation in the presence of ApoE4.

The strongest genetic risk factor for late-onset Alzheimer's disease (AD) is allelic variation of the APOE gene, with the following risk structure: ε4 > ε3 > ε2. The biochemical basis for this risk profile is unclear. Here, we reveal a new role for the APOE gene product, apolipoprotein E (ApoE) in regulating cellular copper homeostasis, which is perturbed in the AD brain. Exposure of ApoE target replacement (TR) astrocytes (immortalised astrocytes from APOE knock-in mice) to elevated copper concentrations resulted in exacerbated copper accumulation in ApoE4- compared to ApoE2- and ApoE3-TR astrocytes. This effect was also observed in SH-SY5Y neuroblastoma cells treated with conditioned medium from ApoE4-TR astrocytes. Increased intracellular copper levels in the presence of ApoE4 may be explained by reduced levels and delayed trafficking of the copper transport protein, copper-transporting ATPase 1 (ATP7A/Atp7a), potentially leading to impaired cellular copper export. This new role for ApoE in copper regulation lends further biochemical insight into how APOE genotype confers risk for AD and reveals a potential contribution of ApoE4 to the copper dysregulation that is a characteristic pathological feature of the AD brain.

Phenotypic and mutational spectrum of 17 Chinese patients with Menkes Disease.

BACKGROUND: Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival. OBJECTIVE: This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients. METHODS: Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients. RESULTS: All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3-4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21-48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel. CONCLUSIONS: Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.

The physiological and pathophysiological roles of copper in the nervous system.

Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-ß-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling.

Cupric-polymeric nanoreactors integrate into copper metabolism to promote chronic diabetic wounds healing.

Given multifunction of copper (Cu) contributing to all stages of the physiology of wound healing, Cu-based compounds have great therapeutic potentials to accelerate the wound healing, but they must be limited to a very low concentration range to avoid detrimental accumulation. Additionally, the cellular mechanism of Cu-based compounds participating the healing process remains elusive. In this study, copper oxide nanoparticles (CuONPs) were synthesized to mimic the multiple natural enzymes and trapped into PEG-b-PCL polymersomes (PS) to construct cupric-polymeric nanoreactors (CuO@PS) via a direct hydration method, thus allowing to compartmentalize Cu-based catalytic reactions in an isolated space to improve the efficiency, selectivity, recyclability as well as biocompatibility. While nanoreactors trafficked to lysosomes following endocytosis, the released Cu-based compounds in lysosomal lumen drove a cytosolic Cu+ influx to mobilize Cu metabolism mostly via Atox1-ATP7a/b-Lox axis, thereby activating the phosphorylation of mitogen-activated protein kinase 1 and 2 (MEK1/2) to initiate downstream signaling events associated with cell proliferation, migration and angiogenesis. Moreover, to facilitate to lay on wounds, cupric-polymeric nanoreactors were finely dispersed into a thermosensitive Pluronic F127 hydrogel to form a composite hydrogel sheet that promoted the healing of chronic wounds in diabetic rat models. Hence, cupric-polymeric nanoreactors represented an attractive translational strategy to harness cellular Cu metabolism for chronic wounds healing.

Investigation of cuproptosis regulator-mediated modification patterns and SLC30A7 function in GBM.

BACKGROUND: Copper-dependent controlled cell death (cuproptosis) is a novel cell death modality that is distinct from known cell death mechanisms. Nonetheless, the potential role of the cuproptosis regulator in tumour microenvironment (TME) of GBM remains unknown. METHODS: Based on 13 widely recognised cuproptosis regulators, the cuproptosis regulation patterns and the biological characteristics of each pattern were comprehensively assessed in GBMs. Machine learning strategies were used to construct a CupScore to quantify the cuproptosis regulation patterns of individual tumours. A PPI network was constructed to predict core-associated genes of cuproptosis regulators. The function of the novel cuproptosis regulators SLC30A7 was examined by in vitro and in vivo experiment. RESULTS: We identified three distinct cuproptosis regulation patterns, including immune activation, metabolic activation, and immunometabolic double deletion patterns. The CupScore was shown to predict the abundance of tumour inflammation, molecular subtype, stromal activity, gene variation, signalling pathways, and patient prognosis. The low CupScore subtype was characterised by immune activation, isocitrate dehydrogenase mutations, sensitivity to chemotherapy, and clinical benefits. The high CupScore subtype was characterised by activation of the stroma and metabolism and poor survival. Novel cuproptosis regulator SLC30A7 knockdown inhibited the cuproptosi via JAK2/STAT3/ATP7A pathway in GBM. CONCLUSION: Cuproptosis regulators have been shown to play a vital role in TME complexity. Constructing CupScores were trained to evaluate the regulation patterns of cuproptosis in individual tumours. The novel cuproptosis-related genes SLC30A7 was involved in regulation the tumorigenicity of GBM cell via JAK2/STAT3/ATP7A pathway in vitro and in vivo.

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.

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.

Clinical features of Menkes disease(report of one case) / 临床神经病学杂志

Objective To investigate the clinical features of Menkes disease(MD)caused by ATP7A gene mutation.Methods Clinical data of one MD patient was retrospectively analyzed,and the literature on the MD cases was reviewed.Results The patient was a 7-month-old male.The initial symptoms were epilepsy,feeding difficulties and psychomotor retardation,followed by distinctive facial appearance,hair abnormality,pectus excavatum and hypotonia.Biochemical tests revealed reduced serum ceruloplasmin and copper.Brain MRI showed diffuse cerebral atrophy,cerebral dysplasia and subdural effusion.Genetic testing showed that there was a new hemizygous mutation c.2916+2(IVS14)T＞C in the ATP7A gene splicing site on the X chromosome,which verified that the mother was a heterozygous carrier with a normal phenotype.Conclusions MD often starts in infancy and childhood.MD may involve multi-system such as the nervous system and connective tissues,and should be diagnosed with genetic testing.

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.

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.

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.

Genetic diversity, tissue-specific expression, and functional analysis of the ATP7A gene in sheep.

In humans, variation of the ATP7A gene may cause cranial exostosis, which is similar to "human horn," but the function of the ATP7A gene in sheep is still unknown. Tissue expression patterns and potential functional loci analysis of the ATP7A gene could help understand its function in sheep horn. In this study, we first identified tissue, sex, breed, and species-specific expression of the ATP7A gene in sheep based on the RNA-sequencing (RNA-seq) data. Second, the potential functional sites of the ATP7A gene were analyzed by using the whole genome sequencing (WGS) data of 99 sheep from 10 breeds. Last, the allele-specific expression of the ATP7A gene was explored. Our result showed the ATP7A gene has significantly higher expression in the big horn than in the small horn, and the ATP7A gene has high expression in the horn and skin, suggesting that this gene may be related to the horn. The PCA results show that the region around the ATP7A can distinguish horned and hornless groups to some extent, further indicating that the ATP7A may be related to horns. When compared with other species, we find seven ruminate specific amino acid sites of the ATP7A protein, which can be important to the ruminate horn. By analyzing WGS, we found 6 SNP sites with significant differences in frequency in horned and hornless populations, and most of these variants are present in the intron. But we still find some potential functional sites, including three missenses, three synonymous mutations, and four Indels. Finally, by combining the RNA-seq and WGS functional loci results, we find three mutations that showed allele-specific expression between big and small horns. This study shows that the ATP7A gene in sheep may be related to horn size, and several potential functional sites we identified here can be useful molecular markers for sheep horn breeding.

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.

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.

Effect of miR-149-5p on intramuscular fat deposition in pigs based on metabolomics and transcriptomics.

As one of the important traits in pig production, meat quality has important research significance and value. Intramuscular fat (IMF) content is one of the most important factors affecting pork quality. Many experimental studies have shown that IMF content is closely related to the flavor, tenderness, and juiciness of pork. Therefore, it is of great significance to study the mechanism of porcine IMF deposition. Previous research indicated that miR-149-5p promoted the proliferation of porcine intramuscular (IM) preadipocytes and decreased their ability to differentiate, albeit the exact mechanism of action is unknown. In vitro, foreign pigs showed increased miR-149-5p expression and reduced fat deposition when compared to Queshan Black pigs. This study conducted metabolomics and transcriptomics analyses of porcine IM preadipocytes overexpressing miR-149-5p to verify their effects on lipid formation. According to metabolomics analysis, the overexpression of miR-149-5p has significantly altered the lipid, organic acid, and organic oxygen metabolites of porcine IM preadipocytes. Specially speaking, it has changed 115 metabolites, including 105 up-regulated and 10 down-regulated ones, as well as the composition of lipid, organic acid, and organic oxygen metabolism-related metabolites. RNA-seq analysis showed that overexpression of miR-149-5p significantly altered 857 genes, of which 442 were up-regulated, and 415 were down-regulated, with enrichment to MAPK, IL-17, PI3K-Akt, and ErbB signaling pathways. We found that overexpression of miR-149-5p inhibited adipogenic differentiation by changing cAMP signaling pathway in porcine IM preadipocytes. In addition, the overexpression of miR-149-5p may affect the transport of Cu2+ by targeting ATP7A and inhibiting adipogenic differentiation. These findings elucidate the regulatory function of miR-149-5p in porcine IM preadipocytes, which may be a key target for controlling pork quality.

Menkes disease complicated by concurrent ACY1 deficiency: A case report.

Introduction: Menkes disease is an X-linked recessive condition caused by mutations in the ATP7A gene, which leads to severe copper deficiency. Aminoacylase-1 deficiency is a rare inborn error of metabolism caused by homozygous or compound heterozygous variant in the ACY1 gene, characterized by increased urinary excretion of specific N-acetyl amino acids. Case presentation: We report an infant with neurological findings such as seizures, neurodevelopmental delay and hypotonia. Metabolic screening showed low serum copper and ceruloplasmin, and increased urinary excretion of several N-acetylated amino acids. Whole-exome sequencing analysis (WES) revealed the novel de novo variant c.3642_3649dup (p.Ala1217Aspfs*2) in the ATP7A gene, leading to a diagnosis of Menkes disease, and the simultaneous presence of the homozygous ACY1 variant c.1057C>T (p.Arg353Cys) causative of Aminoacylase-1 deficiency. Conclusion: Our patient had two rare conditions with different treatment courses but overlapping clinical features. The identified novel ATP7A mutation associated with Menkes disease expands the ATP7A gene spectrum.

Ethics in pre-ART genetics: a missed X-linked Menkes disease case.

Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present.

ATP7A-related copper transport disorders: A systematic review and definition of the clinical subtypes.

In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear genotype-phenotype correlation. We performed a systematic literature review by querying the MEDLINE and Embase databases identifying 143 relevant papers. We recorded data on the phenotype and genotype in 162 individuals with a molecularly confirmed ATP7A-related disorder in order to identify differentiating clinical criteria, evaluate genotype-phenotype correlations and propose management guidelines. Early seizures are specific for classical Menkes disease (CMD), that is characterized by early-onset neurodegenerative disease with high mortality rates. Ataxia is an independent indicator for atypical Menkes disease, that shows better survival rates than CMD. Bony exostoses, radial head dislocations, herniations and dental abnormalities are specific for occipital horn syndrome (OHS) that may further present with developmental delay and connective tissue manifestations. Intracranial tortuosity and bladder diverticula, both with high risk of complications, are common among all subtypes. Low ceruloplasmin is a more sensitive and discriminating biomarker for ATP7A-related disorders than serum copper. Truncating mutations are frequently associated with CMD, in contrast with splice site and intronic mutations which are more prevalent in OHS.

Copper transporter gene ATP7A: A predictive biomarker for immunotherapy and targeted therapy in hepatocellular carcinoma.

BACKGROUND: ATP7A is an important copper transporter that regulates numerous cellular biological processes. However, the role of ATP7A in immunotherapy and targeted therapy, especially for hepatocellular carcinoma (HCC), remains unknown. METHODS: We analyzed ATP7A expression and its effect on digestive system tumor prognoses, assessed its expression in tissue microarrays from 319 HCC patients, and investigated the relationship between ATP7A expression and tumor immunity. Specifically, we evaluated the possible association between ATP7A and programmed death ligand 1 (PD-L1) expression in human HCC tissues. Finally, we analyzed the effect of ATP7A on sorafenib efficacy in HCC. RESULTS: ATP7A is generally highly expressed in digestive system tumors but related to poor prognosis only in HCC. ATP7A levels are positively associated with immune cell infiltration and immune checkpoint expression (especially PD-L1). HCC patients coexpressing APT7A and PD-L1 demonstrate poor prognoses. Moreover, HCC patients with high ATP7A levels were more sensitive to sorafenib and demonstrated higher survival rates after sorafenib treatment. CONCLUSIONS: This study provides insights into the correlation between ATP7A levels and tumor immune infiltration and immune checkpoint function in HCC, sheds light on the significance of ATP7A in cancer progression, and provides guidance for more effective and general therapeutic strategies.

Heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates the abundance of the copper-transporter ATP7A in an isoform-dependent manner.

Copper (Cu) is an essential micronutrient with a critical role in mammalian growth and development. Imbalance of Cu causes severe diseases in humans; therefore, cellular Cu levels are tightly regulated. Major Cu-transport proteins and their cellular behavior have been characterized in detail, whereas their regulation at the mRNA level and associated factors are not well-understood. We show that the heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates Cu homeostasis by modulating the abundance of Cu(I)-transporter ATP7A. Downregulation of hnRNPA2/B1 in HeLa cells increases the ATP7A mRNA and protein levels and significantly decreases cellular Cu; this regulation involves the 3' UTR of ATP7A transcript. Downregulation of B1 and B1b isoforms of hnRNPA2/B1 is sufficient to elevate ATP7A, whereas overexpression of either hnRNPA2 or hnRNPB1 isoforms decreases the ATP7A mRNA levels. Concurrent decrease in hnRNPA2/B1, increase in ATP7A, and a decrease in Cu levels was observed in neuroblastoma SH-SY5Y cells during retinoic acid-induced differentiation; this effect was reversed by overexpression of B1/B1b isoforms. We conclude that hnRNPA2/B1 is a new isoform-specific negative regulator of ATP7A abundance.