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Stephen G Kaler - One of the best experts on this subject based on the ideXlab platform.
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menkes disease and other disorders related to atp7a
2019Co-Authors: Cynthia Abou Zeid, Stephen G KalerAbstract:Abstract The ATP7A-related disorders are a heterogeneous group of diseases resulting from ATP7A (Menkes ATPase) dysfunction. They have varying phenotypes and clinical diseases, depending on the underlying genetic mutations. Some ensue from direct changes in the gene that encodes the ATP7A protein. The severity of the mutations can affect the phenotype expressed. If the mutations are severe loss-of-function mutations, the result is a lethal neurodevelopmental and systemic disease with low copper and reduced cuproenzymes activity (Menkes disease). If the mutations are milder, such as with leaky splice junction defects, some copper transport is possible and the phenotype is less severe, as in Occipital Horn Syndrome. Two unique missense mutations that do not impair the copper transport function of ATP7A but rather its trafficking, cause a motor neuron-specific illness that develops gradually, with no evidence of abnormal copper metabolism. ATP7A function can also be affected by mutations outside of its coding gene, such as in MEDNIK and Huppke–Brendel Syndromes. The resulting defects in intracellular localization of the ATP7A (and ATP7B) pump(s) can impair normal copper transport function.
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interaction between the aaa atpase p97 vcp and a concealed ubx domain in the copper transporter atp7a is associated with motor neuron degeneration
Journal of Biological Chemistry, 2018Co-Authors: Stephen G KalerAbstract:The copper-transporting ATPase ATP7A contains eight transmembrane domains and is required for normal human copper homeostasis. Mutations in the ATP7A gene may lead to infantile-onset cerebral degeneration (Menkes disease); Occipital Horn Syndrome (OHS), a related but much milder illness; or an adult-onset isolated distal motor neuropathy. The ATP7A missense mutation T994I is located in the sixth transmembrane domain of ATP7A, represents one of the variants associated with the latter phenotype, and is associated with an abnormal interaction with p97/valosin-containing protein (VCP), a hexameric AAA ATPase (ATPase associated with diverse cellular activities) with multiple biological functions. In this study, we further characterized this interaction and discovered a concealed UBX domain in the third lumenal loop of ATP7A, between its fifth and sixth transmembrane domains. We show that the T994I substitution results in conformational exposure of the UBX domain, which then binds the N-terminal domain of p97/VCP. We also show that this abnormal interaction occurs at or near the cell plasma membrane. The UBX domain has a conserved hydrophobic FP (Phe-Pro) motif, and substitution with di-alanine abrogated the interaction and restored the proper intracellular localization of ATP7A in the trans-Golgi network. Using protein MS, we identified potential coordinating components of the ATP7AT994I–p97 complex, including NSFL1 cofactor (NSF1C or p47) that may be relevant to the pathophysiology and clinical effects associated with ATP7AT994I. Our study represents the first report of p97/VCP binding to a UBX domain that is not normally exposed, resulting in an aberrant protein–protein interaction leading to motor neuron degeneration.
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direct interactions of adaptor protein complexes 1 and 2 with the copper transporter atp7a mediate its anterograde and retrograde trafficking
Human Molecular Genetics, 2015Co-Authors: Stephen G KalerAbstract:ATP7A is a P-type ATPase in which diverse mutations lead to X-linked recessive Menkes disease or Occipital Horn Syndrome. Recently, two previously unknown ATP7A missense mutations, T994I and P1386S, were shown to cause an isolated distal motor neuropathy without clinical or biochemical features of other ATP7A disorders. These mutant alleles cause subtle defects in ATP7A intracellular trafficking, resulting in preferential plasma membrane localization compared with wild-type ATP7A. We reported previously that ATP7A(P1386S) causes unstable insertion of the eighth and final transmembrane segment, preventing proper position of the carboxyl-terminal tail in a proportion of mutant molecules. Here, we utilize this and other naturally occurring and engineered mutant ATP7A alleles to identify mechanisms of normal ATP7A trafficking. We show that adaptor protein (AP) complexes 1 and 2 physically interact with ATP7A and that binding is mediated in part by a carboxyl-terminal di-leucine motif. In contrast to other ATP7A missense mutations, ATP7A(P1386S) partially disturbs interactions with both APs, leading to abnormal axonal localization in transfected NSC-34 motor neurons and altered calcium-signaling following glutamate stimulation. Our results imply that AP-1 normally tethers ATP7A at the trans-Golgi network in the somatodendritic segments of motor neurons and that alterations affecting the ATP7A carboxyl-terminal tail induce release of the copper transporter to the axons or axonal membranes. The latter effects are intensified by diminished interaction with AP-2, impeding ATP7A retrograde trafficking. Taken together, these findings further illuminate the normal molecular mechanisms of ATP7A trafficking and suggest a pathophysiological basis for ATP7A-related distal motor neuropathy.
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atp7a trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in atp7a
Annals of the New York Academy of Sciences, 2014Co-Authors: Stephen G KalerAbstract:Diverse mutations in the gene encoding the copper transporter ATP7A lead to X-linked recessive Menkes disease or Occipital Horn Syndrome. Recently, two unique ATP7A missense mutations, T994I and P1386S, were shown to cause isolated adult-onset distal motor neuropathy. These mutations induce subtle defects in ATP7A intracellular trafficking resulting in preferential accumulation at the plasma membrane compared to wild-type ATP7A. Immunoprecipitation assays revealed abnormal interaction between ATP7A(T994I) and p97/VCP, a protein mutated in two autosomal dominant forms of motor neuron disease. Small-interfering RNA knockdown of valosin-containing protein corrected ATP7A(T994I) mislocalization. For ATP7A(P1386S) , flow cytometry documented that nonpermeabilized fibroblasts bound a C-terminal ATP7A antibody, suggesting unstable insertion of the eighth transmembrane segment due to a helix-breaker effect of the amino acid substitution. This could sabotage interaction of ATP7A(P1386S) with adaptor protein complexes. These molecular events appear to selectively disturb normal motor neuron function and lead to neurologic illness that takes years and sometimes decades to develop.
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inborn errors of copper metabolism
Handbook of Clinical Neurology, 2013Co-Authors: Stephen G KalerAbstract:Two copper-transporting ATPases are essential for mammalian copper homeostasis: ATP7A, which mediates copper uptake in the gastrointestinal tract and copper delivery to the brain, and ATP7B, which mediates copper excretion by the liver into bile. Mutations in ATP7A may cause three distinct X-linked conditions in infants, children, or adolescents: Menkes disease, Occipital Horn Syndrome (OHS), and a newly identified allelic variant restricted to motor neurons called X-linked distal hereditary motor neuropathy. These three disorders show variable neurological findings and ages of onset. Menkes disease presents in the first several months of life with failure to thrive, developmental delay, and seizures. OHS features more subtle developmental delays, dysautonomia, and connective tissue abnormalities beginning in early childhood. ATP7A-related distal motor neuropathy presents even later, often not until adolescence or early adulthood, and involves a neurological phenotype that resembles Charcot–Marie–Tooth disease, type 2. These disorders may be treatable through copper replacement or ATP7A gene therapy. In contrast, mutations in ATP7B cause a single known phenotype, Wilson disease, an autosomal recessive trait that results from copper overload rather than deficiency. Dysarthria, dystonia, tremor, gait abnormalities, and psychiatric problems may be presenting symptoms, at ages from 10 to 40 years. Excellent treatment options exist for Wilson disease, based on copper chelation. In the past 2 years (2012–2013), three new autosomal recessive copper metabolism conditions have been recognized: 1) Huppke–Brendel Syndrome caused by mutations in an acetyl CoA transporter needed for acetylation of one or more copper proteins, 2) CCS deficiency caused by mutations in the copper chaperone to SODI, and 3) MEDNIK Syndrome, which revealed that mutations in the σ1A subunit of adaptor protein complex 1 (AP-1) have detrimental effects on trafficking of ATP7A and ATP7B.
Hiroko Kodama - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH Open Access Exon duplications in the ATP7A gene: Frequency
2013Co-Authors: Transcriptional Behaviour, Tina Skjørringe, Mie Mogensen, Hiroko Kodama, Kenneth Silver, Nina Horn, Lisbeth B MøllerAbstract:Background: Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the ATP7A gene. Methods: The ATP7A gene was screened for exon duplications using multiplex ligation-dependent probe amplification (MLPA). The expression level of ATP7A was investigated by real-time PCR and detailed analysis of the ATP7A mRNA was performed by RT-PCR followed by sequencing. In order to investigate whether the identified duplicated fragments originated from a single or from two different X-chromosomes, polymorphic markers located in the duplicated fragments were analyzed. Results: Partial ATP7A gene duplication was identified in 20 unrelated patients including one patient with Occipital Horn Syndrome (OHS). Duplications in the ATP7A gene are estimated from our material to be the disease causing mutation in 4 % of the Menkes disease patients. The duplicated regions consist of between 2 and 15 exons. In at least one of the cases, the duplication was due to an intra-chromosomal event. Characterization of the ATP7A mRNA transcripts in 11 patients revealed that the duplications were organized in tandem, in a head to tail direction. The reading frame was disrupted in all 11 cases. Small amounts of wild-type transcript were found in al
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Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, and Treatment
2013Co-Authors: Hiroko Kodama, Chie Fujisawa, Wattanaporn BhadhprasitAbstract:Abstract: Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, Occipital Horn Syndrome, and Wilson’s disease. Menkes disease and Occipital Horn Syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital Horn Syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this Syndrome. Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants. Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention. Keywords: Menkes disease, Wilson’s disease, Occipital Horn Syndrome, ATP7A, ATP7B, disulfiram, zinc, trientine. I
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effects of disulfiram treatment in patients with menkes disease and Occipital Horn Syndrome
Journal of Trace Elements in Medicine and Biology, 2012Co-Authors: Eishin Ogawa, Hiroko KodamaAbstract:The clinical and biochemical effects of disulfiram were evaluated in three boys with the disorders characterized by copper deficiency due to the defect of ATP7A. Two suffered from Menkes disease (MD) and one from Occipital Horn Syndrome. Disulfiram was orally given, in addition to a parenteral administration of copper-histidine in the case of MD patients. Serum levels of copper and ceruloplasmin slightly increased in one MD patient, and he showed favorable emotional expression and behavior more often than before according to his caretakers. However, no obvious changes were observed in the other two patients. Serum ratios of noradrenaline to dopamine, and adrenaline to dopamine, which are thought to be the indicators of dopamine β-hydroxylase activity, one of the copper requiring enzymes, were unaltered after disulfiram treatment. No adverse effects were recognized during the treatment period in all patients. Although the major improvement was not observed clinically or biochemically by disulfiram treatment so far, the trial will be continued to see the possible effects in these disorders with copper transport defect.
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inherited copper transport disorders biochemical mechanisms diagnosis and treatment
Current Drug Metabolism, 2012Co-Authors: Hiroko Kodama, Chie Fujisawa, Wattanaporn BhadhprasitAbstract:Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, Occipital Horn Syndrome, and Wilson's disease. Menkes disease and Occipital Horn Syndrome are characterized by copper deficiency. Typical features of Menkes disease result copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital Horn Syndrome characterized connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this Syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
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copper metabolism and inherited copper transport disorders molecular mechanisms screening and treatment
Metallomics, 2009Co-Authors: Hiroko Kodama, Chie FujisawaAbstract:In this review, we discuss genetic disorders involving altered copper metabolism, particularly in relation to Menkes disease (MD), Occipital Horn Syndrome (OHS), and Wilson’s disease (WD). The responsible genes for MD and WD are ATP7A and ATP7B, respectively. Both proteins encoded by these genes are responsible for transporting copper from the cytosol to the Golgi apparatus. However, the pathology of MD is completely different from that of WD, that is, MD is characterized by a copper deficiency while WD is caused by a toxic excess of copper. The reason for this difference is related to the particular cell types in which the ATP7A and ATP7B proteins are expressed. ATP7A is expressed in almost all cell types except hepatocytes, whereas ATP7B is mainly expressed in hepatocytes. MD and OHS are X-linked recessive disorders characterized by copper deficiency. Typical features of MD, such as neurological disturbances, connective tissue disorders, and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care treatment for MD is parenteral administrations of copper–histidine. When the treatment is initiated in newborn babies prior to two months of age, the neurological degeneration may be prevented, but delayed treatment is considerably less effective. Moreover, copper–histidine treatment does not improve symptoms of the connective tissue disorders. As such, systems for mass screening of neonates for MD should be implemented. At the same time, novel treatments targeting connective tissue disorders need to be developed. OHS is a milder form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to those with MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. The hepatic and nervous systems are typically most severely affected. Numerous other symptoms can also be observed, however, making an early diagnosis difficult. Chelating agents and zinc are effective for the treatment of WD, but they are ineffective for the patients with fulminant hepatic failure. Some patients with neurological diseases show poor response to chelating agents; here again, early diagnosis and treatment are critical. Screening of newborn babies or infants for WD can help lead to timely diagnosis and treatment. Patients with WD may have a risk of hepatocellular carcinoma despite receiving treatment. An understanding of the relation between WD and hepatocellular carcinoma will provide clues to help prevent hepatocellular carcinoma in patients with WD.
Seymour Packman - One of the best experts on this subject based on the ideXlab platform.
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inherited disorders of human copper metabolism
Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013Co-Authors: Stephen G Kaler, Seymour PackmanAbstract:Copper is a trace element of essential importance to humans. Our need for copper relates to its role as a cofactor for a number of enzymes whose activities are responsible for critical cellular processes. Numerous conditions can influence copper homeostasis and serum copper levels, including several genetic diseases described in this chapter. Spawned by identification of the genes responsible for Menkes disease and Wilson disease, the past two decades have witnessed a remarkable growth in our knowledge and understanding of eukaryotic copper metabolism. Appreciation of the basic pathways that guide cellular copper uptake, transport, and export has reached a reasonable level; however, considerably less is known about the precise mechanisms that underlie the neurological consequences of disturbed copper homeostasis, and the ideal remedies. Mutations in the copper-transporting ATPase, ATP7A, yield three distinct X-linked Syndromes—Menkes disease, Occipital Horn Syndrome, and isolated distal motor neuropathy—whereas defects in ATP7B cause autosomal recessive Wilson disease. Numerous examples of infantile copper toxicosis have been reported globally. Environmental exposures to copper often contribute to this Syndrome, for which the genetic bases remain obscure. An array of useful animal models provides opportunities for further exploration of human copper metabolism and evaluation of potential disease remedies for inherited copper transport disorders, including gene therapy.
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a repeated element in the regulatory region of the mnk gene and its deletion in a patient with Occipital Horn Syndrome
Human Molecular Genetics, 1996Co-Authors: Barbara Levinson, Seymour Packman, Rebecca Conant, Rhonda E Schnur, Soma Das, Jane GitschierAbstract:Occipital Horn Syndrome (OHS), an X-linked connective tissue disorder, has recently been shown to result from mutations in the Menkes disease gene (MNK), which encodes a copper-transporting ATPase. By Southern analysis we detected a small deletion in a region 5' to the MNK gene in one patient with OHS. Genomic clones from an unaffected individual were isolated and sequenced, revealing three tandem 98 bp repeats situated upstream of the reported transcription start site, and analysis of the patient's DNA showed a deletion of one of the repeats. The deletion is likely to be responsible for the disease in this patient, as it was not observed in 110 unaffected individuals analyzed, and no other mutation in the patient was detected by RT-PCR and chemical cleavage mismatch analysis or by cDNA sequence analysis. The deletion is associated with a dramatic decrease in expression of a chloramphenicol acetyltransferase reporter gene, implicating the repeat sequences in regulation of MNK expression, although a quantitative analysis of MNK mRNA from a cell line derived from the patient shows no detectable reduction. Other experiments revealed no effect on the site of transcription initiation, termination or on splicing.
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similar splicing mutations of the menkes mottled copper transporting atpase gene in Occipital Horn Syndrome and the blotchy mouse
American Journal of Human Genetics, 1995Co-Authors: S Das, Barbara Levinson, Chris D Vulpe, S Whitney, Jane Gitschier, Seymour PackmanAbstract:The connective-tissue disorder Occipital Horn Syndrome (OHS) is hypothesized to be allelic to Menkes disease. The two diseases have different clinical presentations but have a similar abnormality of copper transport. Mice hemizygous for the blotchy allele of the X-linked mottled locus have similar connective-tissue defects as OHS and may represent a mouse model of this disease. We have analyzed the Menkes/mottled copper-transporting ATPase in these two potentially homologous disorders and have identified similar splicing mutations in both. Some expression of normal mRNA was detectable by reverse transcription-PCR in the mutant tissues. These findings contrast with the more debilitating mutations observed in Menkes disease and suggest that low amounts of an otherwise normal protein product could result in the relatively mild phenotype of OHS and of the blotchy mouse.
Chie Fujisawa - One of the best experts on this subject based on the ideXlab platform.
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Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, and Treatment
2013Co-Authors: Hiroko Kodama, Chie Fujisawa, Wattanaporn BhadhprasitAbstract:Abstract: Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, Occipital Horn Syndrome, and Wilson’s disease. Menkes disease and Occipital Horn Syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital Horn Syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this Syndrome. Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants. Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention. Keywords: Menkes disease, Wilson’s disease, Occipital Horn Syndrome, ATP7A, ATP7B, disulfiram, zinc, trientine. I
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inherited copper transport disorders biochemical mechanisms diagnosis and treatment
Current Drug Metabolism, 2012Co-Authors: Hiroko Kodama, Chie Fujisawa, Wattanaporn BhadhprasitAbstract:Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, Occipital Horn Syndrome, and Wilson's disease. Menkes disease and Occipital Horn Syndrome are characterized by copper deficiency. Typical features of Menkes disease result copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital Horn Syndrome characterized connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this Syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
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copper metabolism and inherited copper transport disorders molecular mechanisms screening and treatment
Metallomics, 2009Co-Authors: Hiroko Kodama, Chie FujisawaAbstract:In this review, we discuss genetic disorders involving altered copper metabolism, particularly in relation to Menkes disease (MD), Occipital Horn Syndrome (OHS), and Wilson’s disease (WD). The responsible genes for MD and WD are ATP7A and ATP7B, respectively. Both proteins encoded by these genes are responsible for transporting copper from the cytosol to the Golgi apparatus. However, the pathology of MD is completely different from that of WD, that is, MD is characterized by a copper deficiency while WD is caused by a toxic excess of copper. The reason for this difference is related to the particular cell types in which the ATP7A and ATP7B proteins are expressed. ATP7A is expressed in almost all cell types except hepatocytes, whereas ATP7B is mainly expressed in hepatocytes. MD and OHS are X-linked recessive disorders characterized by copper deficiency. Typical features of MD, such as neurological disturbances, connective tissue disorders, and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care treatment for MD is parenteral administrations of copper–histidine. When the treatment is initiated in newborn babies prior to two months of age, the neurological degeneration may be prevented, but delayed treatment is considerably less effective. Moreover, copper–histidine treatment does not improve symptoms of the connective tissue disorders. As such, systems for mass screening of neonates for MD should be implemented. At the same time, novel treatments targeting connective tissue disorders need to be developed. OHS is a milder form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to those with MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. The hepatic and nervous systems are typically most severely affected. Numerous other symptoms can also be observed, however, making an early diagnosis difficult. Chelating agents and zinc are effective for the treatment of WD, but they are ineffective for the patients with fulminant hepatic failure. Some patients with neurological diseases show poor response to chelating agents; here again, early diagnosis and treatment are critical. Screening of newborn babies or infants for WD can help lead to timely diagnosis and treatment. Patients with WD may have a risk of hepatocellular carcinoma despite receiving treatment. An understanding of the relation between WD and hepatocellular carcinoma will provide clues to help prevent hepatocellular carcinoma in patients with WD.
Lisbeth Birk Møller - One of the best experts on this subject based on the ideXlab platform.
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Occipital Horn Syndrome as a result of splice site mutations in atp7a no activity of atp7a splice variants missing exon 10 or exon 15
Frontiers in Molecular Neuroscience, 2021Co-Authors: Lisbeth Birk Møller, Mie Mogensen, David D Weaver, Per Amstrup PedersenAbstract:Disease-causing variants in ATP7A lead to two different phenotypes associated with copper deficiency; a lethal form called Menkes disease (MD), leading to early death, and a much milder form called Occipital Horn Syndrome (OHS). Some investigators have proposed that an ATP7A transcript missing exon 10 leads to a partly active protein product resulting in the OHS phenotype. Here, we describe an individual with OHS, a biology professor, who survived until age 62 despite a splice site mutation, leading to skipping of exon 15. ATP7A transcripts missing exon 10, or exon 15 preserve the reading frame, but it is unknown if either of these alternative transcripts encode functional protein variants. We have investigated the molecular consequence of splice site mutations leading to skipping of exon 10 or exon 15 which have been identified in individuals with OHS, or MD. By comparing ATP7A expression in fibroblasts from three individuals with OHS (OHS-fibroblasts) to ATP7A expression in fibroblasts from two individuals with MD (MD-fibroblasts), we demonstrate that transcripts missing either exon 10 or exon 15 were present in similar amounts in OHS-fibroblasts and MD-fibroblasts. No ATP7A protein encoded from these transcripts could be detected in the OHS and MD fibroblast. These results, combined with the observation that constructs encoding ATP7A cDNA sequences missing either exon 10, or exon 15 were unable to complement the high iron requirement of the ccc2Δ yeast strain, provide evidence that neither a transcript missing exon 10 nor a transcript missing exon 15 results in functional ATP7A protein. In contrast, higher amounts of wild-type ATP7A transcript were present in the OHS-fibroblasts compared with the MD-fibroblasts. We found that the MD-fibroblasts contained between 0 and 0.5% of wild-type ATP7A transcript, whereas the OHS-fibroblasts contained between 3 and 5% wild-type transcripts compared with the control fibroblasts. In summary these results indicate that protein variants encoded by ATP7A transcripts missing either exon 10 or exon 15 are not functional and not responsible for the OHS phenotype. In contrast, expression of only 3-5% of wild-type transcript compared with the controls permits the OHS phenotype.
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Occipital Horn Syndrome and classical Menkes Syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon
European journal of human genetics : EJHG, 2013Co-Authors: Saiqa Yasmeen, Katrine Lund, Anne De Paepe, Sylvia De Bie, Arvid Heiberg, João Silva, Márcia Martins, Tina Skjørringe, Lisbeth Birk MøllerAbstract:Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9% of the patients exhibit a milder form of Menkes disease. The mildest form is called Occipital Horn Syndrome (OHS). Mutations in the ATP7A gene can be identified in 95–98% of the Menkes disease patients by standard screening techniques. Investigation of RNA isolated from the fibroblasts of eleven patients with no identified mutations was performed, and revealed inclusion of new pseudo-exons into the ATP7A mRNA from three unrelated patients: two patients with OHS and one patient with classical Menkes disease. The pseudo-exons were inserted between exons 10 and 11, between exons 16 and 17 and between exons 14 and 15 in the three patients, as a result of deep intronic mutations. This is the first time the activation of pseudo-exons is demonstrated in the ATP7A gene, and it demonstrates the usefulness of RNA analysis, in terms of revealing disease-causing mutations in noncoding regions. The fact that three different mutations cause disease by the activation of pseudo-exon inclusion also indicates that in Menkes disease this is an important mechanism, which has hitherto been overlooked.
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Splice site mutations in the ATP7A gene.
PLOS ONE, 2011Co-Authors: Tina Skjørringe, Zeynep Tumer, Lisbeth Birk MøllerAbstract:Menkes disease (MD) is caused by mutations in the ATP7A gene. We describe 33 novel splice site mutations detected in patients with MD or the milder phenotypic form, Occipital Horn Syndrome. We review these 33 mutations together with 28 previously published splice site mutations. We investigate 12 mutations for their effect on the mRNA transcript in vivo. Transcriptional data from another 16 mutations were collected from the literature. The theoretical consequences of splice site mutations, predicted with the bioinformatics tool Human Splice Finder, were investigated and evaluated in relation to in vivo results. Ninety-six percent of the mutations identified in 45 patients with classical MD were predicted to have a significant effect on splicing, which concurs with the absence of any detectable wild-type transcript in all 19 patients investigated in vivo. Sixty-seven percent of the mutations identified in 12 patients with milder phenotypes were predicted to have no significant effect on splicing, which concurs with the presence of wild-type transcript in 7 out of 9 patients investigated in vivo. Both the in silico predictions and the in vivo results support the hypothesis previously suggested by us and others, that the presence of some wild-type transcript is correlated to a milder phenotype.
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variable clinical expression of an identical mutation in the atp7a gene for menkes disease Occipital Horn Syndrome in three affected males in a single family
The Journal of Pediatrics, 2004Co-Authors: Bettina Borm, Lisbeth Birk Møller, Nina Horn, Kurt Baerlocher, Ingrid Hausser, Michael Emeis, Rainer RossiAbstract:Two maternal half-brothers presented with huge cephalic hematoma, fatal in one. Skin morphology disclosed lack of elastic fibres. Their maternal uncle is moderately mentally handicapped and has extensive connective tissue disorders. In all these patients, an identical missense mutation in the ATP7A gene was found and confirmed Menkes' disease.
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disturbed copper transport in humans part 1 mutations of the atp7a gene lead to menkes disease and Occipital Horn Syndrome
Cellular and Molecular Biology, 2001Co-Authors: J. Seidel, Lisbeth Birk Møller, S. Vogt, H J Mentzel, Eberhard Kauf, Steffi Patzer, Uwe Wollina, F Zintl, Nina HornAbstract:Mutations of the ATP7A gene (OMIM 300011) lead to the Menkes disease (MD, OMIM 309400) involving impaired brain development, neurological degeneration, connective tissue abnormalities, and high lethality in early infancy. Occipital Horn Syndrome (OHS, OMIM 304150), a milder phenotype, is also caused by ATP7A gene mutations. In MD patients, an early copper-histidine treatment may prevent the neurological impairment and prolong survival leading to an OHS phenotype. To demonstrate the genotype/phenotype correlation, two male patients are reported with different ATP7A gene mutations and several phenotypes. In the first patient with the MD phenotype, a mutation within the exon 20 (Gln1288Ter) was found producing a stop codon just prior to the highly conserved ATP binding domain. The OHS phenotype of the second patient was caused by a splice site mutation involving the position +6 of intron 6 within a copper binding domain. Small amounts of correctly spliced ATP7A transcript were sufficient to develop the milder OHS phenotype in this patient (OMIM 30001.0006). In conclusion, mutations of the copper transporting P-type ATPase ATP7A gene cause distinct human diseases showing some genotype/phenotype correlation and implications for treatment.
