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In the past decade, evidence for numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson disease, which paved ways to novel approaches to their treatment. Discovery of cuproptosis and the role of Cu in cells metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology, and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism, in cells' functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.
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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.
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BACKGROUND: Menkes disease (MD) is a rare, inherited, multisystemic copper metabolism disorder. Classical Menkes disease is characterized by low serum copper and ceruloplasmin concentrations, leading to multiple abnormalities in the whole-body, especially in connective tissue and central nervous system. However, serum copper and ceruloplasmin levels are not reliable diagnostic biomarkers due to the low concentrations in healthy newborns either. The featured imaging manifestations play an important role in diagnosing Menkes disease. To our knowledge, there are few reports on the systemic imaging manifestations of Menkes disease. CASE PRESENTATION: A 4-month-old male patient presented with recurrent seizures. He had cognitive, intellectual, growth, gross motor, precision movement, and language developmental lags. The patient's hemoglobin and serum ceruloplasmin level were low. On MRI, increased intracranial vascular tortuosity, cerebral and cerebellar atrophy, white matter changes, and basal ganglia abnormalities were observed. Plain radiograph revealed wormian bones, rib flaring, metaphyseal spurring, and periosteal reactions in the long bones of the limbs. A pathogenic variant in ATP7A gene was identified in the patient, so he was confirmed the diagnosis of Menkes disease. His symptoms did not improve despite symptomatic and supportive treatment during his hospitalization. Unfortunately, the infant died 3 months after leaving hospital. CONCLUSION: A comprehensive and intuitive understanding of the disease's imaging manifestations can help clinicians to identify the disease and avoid delays in care.
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Imagen por Resonancia Magnética , Síndrome del Pelo Ensortijado , Humanos , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/diagnóstico por imagen , Masculino , Lactante , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen de Cuerpo Entero , Huesos/diagnóstico por imagenRESUMEN
Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.
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Transportador de Cobre 1 , Degeneración Hepatolenticular , Síndrome del Pelo Ensortijado , Humanos , Lactante , Recién Nacido , Ceruloplasmina/genética , Cobre , Transportador de Cobre 1/genética , ATPasas Transportadoras de Cobre/genética , Degeneración Hepatolenticular/genética , Síndrome del Pelo Ensortijado/genética , Mutación MissenseRESUMEN
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.
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Cutis Laxo , Síndrome del Pelo Ensortijado , Enfermedades Neurodegenerativas , Humanos , Cobre/metabolismo , ATPasas Transportadoras de Cobre/genética , Cutis Laxo/genética , Mutación , Fragmentos de Péptidos/genéticaRESUMEN
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.
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Síndrome del Pelo Ensortijado , Síndrome del Pelo Ensortijado/genética , Cromosomas Humanos X , Técnicas Reproductivas Asistidas , Humanos , Masculino , Femenino , Embarazo , Persona de Mediana Edad , Resultado del EmbarazoRESUMEN
Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.
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Cobre/metabolismo , Homeostasis/fisiología , Animales , Transporte Biológico/fisiología , ATPasas Transportadoras de Cobre/metabolismo , Humanos , Enfermedades Metabólicas/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Neurodegenerativas/metabolismoRESUMEN
Copper is controlled by a sophisticated network of transport and storage proteins within mammalian cells, yet its uptake and efflux occur with rapid kinetics. Present as Cu(I) within the reducing intracellular environment, the nature of this labile copper pool remains elusive. While glutathione is involved in copper homeostasis and has been assumed to buffer intracellular copper, we demonstrate with a ratiometric fluorescent indicator, crisp-17, that cytosolic Cu(I) levels are buffered to the vicinity of 1 aM, where negligible complexation by glutathione is expected. Enabled by our phosphine sulfide-stabilized phosphine (PSP) ligand design strategy, crisp-17 offers a Cu(I) dissociation constant of 8 aM, thus exceeding the binding affinities of previous synthetic Cu(I) probes by four to six orders of magnitude. Two-photon excitation microscopy with crisp-17 revealed rapid, reversible increases in intracellular Cu(I) availability upon addition of the ionophoric complex CuGTSM or the thiol-selective oxidant 2,2'-dithiodipyridine (DTDP). While the latter effect was dramatically enhanced in 3T3 cells grown in the presence of supplemental copper and in cultured Menkes mutant fibroblasts exhibiting impaired copper efflux, basal Cu(I) availability in these cells showed little difference from controls, despite large increases in total copper content. Intracellular copper is thus tightly buffered by endogenous thiol ligands with significantly higher affinity than glutathione. The dual utility of crisp-17 to detect normal intracellular buffered Cu(I) levels as well as to probe the depth of the labile copper pool in conjunction with DTDP provides a promising strategy to characterize perturbations of cellular copper homeostasis.
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Cobre/metabolismo , Síndrome del Pelo Ensortijado/metabolismo , Tampones (Química) , Fibroblastos/metabolismo , Colorantes Fluorescentes , Glutatión/metabolismo , Ligandos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Mutación , Fosfinas/metabolismoRESUMEN
Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the primary urine and release to the blood. These cells are equipped on their apical and basal membrane with copper transporters CTR1 and ATP7A. Mosaic mutant mice displaying a functional dysfunction of ATP7A are an established model of Menkes disease. These mice exhibit systemic copper deficiency despite renal copper overload, enhanced by copper therapy, which is indispensable for their life span extension. The aim of this study was to analyze the expression of Slc31a1 and Slc31a2 genes (encoding CTR1/CTR2 proteins) and the cellular localization of the CTR1 protein in suckling, young and adult mosaic mutants. Our results indicate that in the kidney of both intact and copper-injected 14-day-old mutants showing high renal copper content, CTR1 mRNA level is not up-regulated compared to wild-type mice given a copper injection. The expression of the Slc31a1 gene in 45-day-old mice is even reduced compared with intact wild-type animals. In suckling and young copper-injected mutants, the CTR1 protein is relocalized from the apical membrane to the cytoplasm of epithelial cells of proximal tubules, the process which prevents copper transport from the primary urine and, thus, protects cells against copper toxicity.
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Transportador de Cobre 1 , Cobre , Células Epiteliales , Túbulos Renales Proximales , Síndrome del Pelo Ensortijado , Animales , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Cobre/metabolismo , Cobre/toxicidad , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , ATPasas Transportadoras de Cobre/genética , ATPasas Transportadoras de Cobre/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Expresión Génica , Túbulos Renales Proximales/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Síndrome del Pelo Ensortijado/etiología , Síndrome del Pelo Ensortijado/genética , Síndrome del Pelo Ensortijado/metabolismo , Ratones , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología , ARN Mensajero/metabolismo , Proteínas SLC31/genética , Proteínas SLC31/metabolismoRESUMEN
PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.
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Complejos de Coordinación/farmacocinética , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Tiosemicarbazonas/farmacocinética , Administración Oral , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C3H , Tamaño de la PartículaRESUMEN
Genetic disorders are in the differential diagnosis when young children present with unexplained fractures or intracranial hemorrhage. For medical and legal reasons, it is imperative to make the correct diagnosis and provide clear, evidence-based explanations of how alternative diagnoses were ruled out. A genetics consultation in cases of suspected child physical abuse should synthesize the history of present illness, medical history, family history, physical examination, and radiologic and laboratory findings in consultation with other specialists. The medical geneticist highlights how these disorders truly present. When the natural history of a genetic disorder is understood, it becomes clear that genetic disorders are not mysterious or difficult to diagnose. As highlighted in this case-based review, mainstream medical practice allows for differentiation among the intracranial and skeletal manifestations of osteogenesis imperfecta, Menkes disease, glutaric acidemia type 1 and child physical abuse. This review also highlights how a genetic disorder, Ehlers-Danlos syndrome, can be misused in a courtroom. Finally, this review summarizes when genetic testing is appropriate in cases of suspected child physical abuse.
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Maltrato a los Niños , Síndrome de Ehlers-Danlos , Fracturas Óseas , Osteogénesis Imperfecta , Niño , Maltrato a los Niños/diagnóstico , Preescolar , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/genética , Hematoma Subdural/diagnóstico por imagen , Hematoma Subdural/genética , Humanos , Lactante , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/genéticaRESUMEN
The copper (Cu) transporters ATPase copper-transporting alpha (ATP7A) and ATPase copper-transporting beta (ATP7B) are essential for the normal function of the mammalian central nervous system. Inactivation of ATP7A or ATP7B causes the severe neurological disorders, Menkes disease and Wilson disease, respectively. In both diseases, Cu imbalance is associated with abnormal levels of the catecholamine-type neurotransmitters dopamine and norepinephrine. Dopamine is converted to norepinephrine by dopamine-ß-hydroxylase (DBH), which acquires its essential Cu cofactor from ATP7A. However, the role of ATP7B in catecholamine homeostasis is unclear. Here, using immunostaining of mouse brain sections and cultured cells, we show that DBH-containing neurons express both ATP7A and ATP7B. The two transporters are located in distinct cellular compartments and oppositely regulate the export of soluble DBH from cultured neuronal cells under resting conditions. Down-regulation of ATP7A, overexpression of ATP7B, and pharmacological Cu depletion increased DBH retention in cells. In contrast, ATP7B inactivation elevated extracellular DBH. Proteolytic processing and the specific activity of exported DBH were not affected by changes in ATP7B levels. These results establish distinct regulatory roles for ATP7A and ATP7B in neuronal cells and explain, in part, the lack of functional compensation between these two transporters in human disorders of Cu imbalance.
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Encéfalo/enzimología , ATPasas Transportadoras de Cobre/biosíntesis , Dopamina beta-Hidroxilasa/metabolismo , Regulación Enzimológica de la Expresión Génica , Neuronas/enzimología , Animales , Encéfalo/citología , Cobre/metabolismo , ATPasas Transportadoras de Cobre/genética , Dopamina beta-Hidroxilasa/genética , Ratones , Neuronas/citología , ProteolisisRESUMEN
Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential disease-modifying treatment of Menkes disease for decades. However, recent evidence suggests its efficacy only when treatment is started within days after birth, which also has important implications related to the techniques that enable early diagnosis. We aim at proposing a guideline for prenatal and neonatal diagnosis and for disease-modifying treatment of Menkes disease, guided by a systematic review of the literature, and built in conjunction with medical experts, methodologists and patient representatives. Thirteen articles were used for our recommendations that were based on GRADE system. Reviewed evidence suggests that prenatal genetic diagnosis in families with previous diagnosis of Menkes disease is feasible; analysis of plasma catecholamine levels is accurate for neonatal diagnosis of Menkes disease; treatment with copper-histidine is effective to increase survival and reduce neurologic burden of the disease if initiated in the neonatal period; and, treatment indication should not be guided by patient's genotype. In conclusion, our guideline can contribute to standardize some aspects of the clinical care of patients with Menkes disease, especially reducing disease burden and mortality and providers' and families' anxiety.
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Cobre/metabolismo , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Diagnóstico Prenatal , Catecolaminas/sangre , Ensayos Clínicos como Asunto , Cobre/uso terapéutico , Diagnóstico Precoz , Femenino , Humanos , Masculino , Síndrome del Pelo Ensortijado/genética , Mutación , EmbarazoRESUMEN
Research on the interplay between iron and copper metabolism in humans began to flourish in the mid-20th century, and diseases associated with dysregulated homeostasis of these essential trace minerals are common even today. Iron deficiency is the most frequent cause of anemia worldwide, leading to significant morbidity, particularly in developing countries. Iron overload is also quite common, usually being the result of genetic mutations which lead to inappropriate expression of the iron-regulatory hormone hepcidin. Perturbations of copper homeostasis in humans have also been described, including rare genetic conditions which lead to severe copper deficiency (Menkes disease) or copper overload (Wilson disease). Historically, the common laboratory rat (Rattus norvegicus) was the most frequently utilized species to model human physiology and pathophysiology. Recently, however, the development of genetic-engineering technology combined with the worldwide availability of numerous genetically homogenous (i.e., inbred) mouse strains shifted most research on iron and copper metabolism to laboratory mice. This created new opportunities to understand the function of individual genes in the context of a living animal, but thoughtful consideration of whether mice are the most appropriate models of human pathophysiology was not necessarily involved. Given this background, this review is intended to provide a guide for future research on iron- and copper-related disorders in humans. Generation of complementary experimental models in rats, swine, and other mammals is now facile given the advent of newer genetic technologies, thus providing the opportunity to accelerate the identification of pathogenic mechanisms and expedite the development of new treatments to mitigate these important human disorders.
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Cobre/metabolismo , Hierro/metabolismo , Modelos Animales , Anemia Ferropénica/genética , Anemia Ferropénica/metabolismo , Animales , DietaRESUMEN
Menkes disease (MD) usually presents in infancy with respiratory and neurological complications. Severe isolated vasculo-connective tissue involvement in infancy is rare, and hence the precise and timely diagnosis is difficult. We report a case of an 8-week-old male infant who succumbed to acute, severe exsanguination, and hemorrhagic shock secondary to a large retroperitoneal hematoma due to rupture of a right iliac artery aneurysm. Perimortem musculoskeletal findings raised suspicion of nonaccidental injury. However, postmortem review of facial traits raised the suspicion of MD. MD was subsequently confirmed on genetic testing. Child health clinicians must remain aware of MD as a rare cause of infant vasculopathy or atypical skeletal abnormalities.
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Aneurisma Roto/etiología , Aneurisma Ilíaco/etiología , Síndrome del Pelo Ensortijado/complicaciones , Exsanguinación/etiología , Resultado Fatal , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis. METHODS: A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK. RESULTS: We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK. CONCLUSION: Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.
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ATPasas Transportadoras de Cobre/genética , Pruebas Genéticas/métodos , Síndrome del Pelo Ensortijado/genética , Pueblo Asiatico/genética , Femenino , Humanos , Recién Nacido , Japón , Masculino , MutaciónRESUMEN
BACKGROUND: Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic "kinky" hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications. METHODS: A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records. RESULTS: All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up. CONCLUSION: Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.
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Divertículo/etiología , Síndrome del Pelo Ensortijado/patología , Vejiga Urinaria/anomalías , Preescolar , ATPasas Transportadoras de Cobre/genética , Análisis Mutacional de ADN , Divertículo/diagnóstico por imagen , Femenino , Genotipo , Humanos , Masculino , Síndrome del Pelo Ensortijado/complicaciones , Síndrome del Pelo Ensortijado/genética , Fenotipo , Pronóstico , Estudios Retrospectivos , Ultrasonografía , Vejiga Urinaria/diagnóstico por imagenRESUMEN
Copper is an essential biometal, and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterized are the copper deficiency and toxicity disorders Menkes and Wilson diseases caused by mutations in the p-type Cu-ATPase genes ATP7A and ATP7B, respectively. Missense mutations in the C-terminal portion of ATP7A have also been shown to cause distal motor neuropathy, whereas polymorphisms in ATP7B are associated with increased risk of Alzheimer's disease. We have generated a single, in vivo model for studying multiple pathogenic mutations in ATP7 proteins using Drosophila melanogaster, which has a single orthologue of ATP7A and ATP7B. Four pathogenic ATP7A mutations and two ATP7B mutations were introduced into a genomic ATP7 rescue construct containing an in-frame C-terminal GFP tag. Analysis of the wild type ATP7-GFP transgene confirmed that ATP7 is expressed at the basolateral membrane of larval midgut copper cells and that the transgene can rescue a normally early lethal ATP7 deletion allele to adulthood. Analysis of the gATP7-GFP transgenes containing pathogenic mutations showed that the function of ATP7 was affected, to varying degrees, by all six of the mutations investigated in this study. Of particular interest, the ATP7BK832R Alzheimer's disease susceptibility allele was found, for the first time, to be a loss of function allele. This in vivo system allows us to assess the severity of individual ATP7A/B mutations in an invariant genetic background and has the potential to be used to screen for therapeutic compounds able to restore function to faulty copper transport proteins.
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Enfermedad de Alzheimer/etiología , Proteínas de Transporte de Catión/genética , Drosophila melanogaster/genética , Degeneración Hepatolenticular/etiología , Síndrome del Pelo Ensortijado/etiología , Neuronas Motoras/patología , Mutación/genética , Animales , ATPasas Transportadoras de Cobre , Modelos Animales de Enfermedad , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Femenino , Masculino , Neuronas Motoras/metabolismoRESUMEN
Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other pathologies. In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. Using fibroblasts from Menkes disease patients and mouse 3T3-L1 cells with a CRISPR/Cas9-inactivated ATP7A, we demonstrate that ATP7A dysfunction is also damaging to mitochondrial redox balance. In these cells, copper accumulates in nuclei, cytosol, and mitochondria, causing distinct changes in their redox environment. Quantitative imaging of live cells using GRX1-roGFP2 and HyPer sensors reveals highest glutathione oxidation and elevation of H2O2 in mitochondria, whereas the redox environment of nuclei and the cytosol is much less affected. Decreasing the H2O2 levels in mitochondria with MitoQ does not prevent glutathione oxidation; i.e. elevated copper and not H2O2 is a primary cause of glutathione oxidation. Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia).