Copper deficiency in the mitochondria of cultured skin fibroblasts from patients with menkes syndrome

Kodama, Hiroko; Okabe, Ichiro; Yanagisawa, Mitsuru; Kodama, Yasuo

doi:10.1007/bf01802032

Cited by 34 publications

(27 citation statements)

References 12 publications

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“…Biochemical analysis has revealed that Cu, in the form of metallothionein-Cu, accumulates in the cytosol of the cells of patients with Menkes' disease and animal models (8.21-23). Moreover, we reported previously that the mitochondria of cultured fibroblasts from patients with Menkes' disease are in a state of Cu deficiency even though the Cu level of the whole cells is high (24). Our present results support these biochemical findings and suggest that the Menkes' mutation affects Cu transport from the cytosol to the organelles in the cell.…”

Section: Discussionsupporting

confidence: 91%

Histochemical localization of copper in the intestine and kidney of macular mice: light and electron microscopic study.

Kodama

Abe²,

Takama³

et al. 1993

J Histochem Cytochem.

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Menkes' disease is an X-linked recessive disorder charaaerized by accumulation of copper in various organs and cells, such as the intestine, kidney, and cultured fibroblasts. Light and electron microscopic localization of Cu was investigated in the intestine and kidney ofmacular mice, an animal model of Menkes' disease, by a modified dide-silver method. Cu was accumulated in the cytoplasm of the absorptive epithelial cells, the vascular endothelium, and secretory granules of the Paneth cells. In kidney the distal tubule cells and glomeruli of both macular and control mice stained faintly, whereas the organelle-free cytoplasm in the proximal tubule

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Section: Discussionsupporting

confidence: 91%

Histochemical localization of copper in the intestine and kidney of macular mice: light and electron microscopic study.

Kodama

Abe²,

Takama³

et al. 1993

J Histochem Cytochem.

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“…We have already observed this pattern in other male patients with MD (11), together with a deficiency in the muscle tissue of the enzyme activity of cytochrome c oxidase, a copper-dependent enzyme. These abnormalities can be explained with a mitochondrial dysfunction due to reduce mitochondrial copper concentrations in mitochondria, as has been observed in fibroblasts of patients (12).…”

Section: Discussionmentioning

confidence: 74%

Lyonization Effects of the t(X;16) Translocation on the Phenotypic Expression in a Rare Female With Menkes Disease

et al. 2009

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Menkes disease (MD) is a rare and severe X-linked recessive disorder of copper metabolism. The MD gene, ATP7A (ATPase Cuϩϩ transporting alpha polypeptide), encodes an ATPdependent copper-binding membrane protein. In this report, we describe a girl with typical clinical features of MD, carrying a balanced translocation between the chromosomes X and 16 producing the disruption of one copy of ATP7A gene and the silencing of the other copy because of the chromosome X inactivation. Fluorescence in situ hybridization experiments with bacterial derived artificial chromosome probes revealed that the breakpoints were located within Xq13.3 and 16p11.2. Replication pattern analysis demonstrated that the normal X chromosome was late replicating and consequently inactivated, whereas the der(X)t(X;16), bearing the disrupted ATP7A gene, was active. An innovative approach, based on FMR1 (fragile X mental retardation 1) gene polymorphism, has been used to disclose the paternal origin of the rearrangement providing a new diagnostic tool for determining the parental origin of defects involving the X chromosome and clarifying the mechanism leading to the cytogenetic rearrangement that occurred in our patient. Menkes disease (MD) is a recessive X-linked syndrome described by Menkes (1) more than 40 y ago. It is characterized by progressive cerebral and cerebellar degeneration, growth retardation, and peculiar scalp hair (2). The incidence is 1/250,000 (ORPHA565, http://www.orpha.net) and, in most of the cases, it is responsible for death before 3 y of age. Patients with MD have been found to have a defect in copper metabolism and low levels of serum copper and ceruloplasmin (3). MD phenotype is due to mutations occurring in the ATP7A (ATPase Cuϩϩ transporting alpha polypeptide) gene, which encodes an ATP-dependent membrane protein (4) that regulates the release of Cu ions at the outer cell membrane, affecting the amount of copper-loaded enzymes, as ceruloplasmin and metallothionein (5).Diagnosis can be established by detecting low levels of copper and ceruloplasmin in the serum, and high levels in cutaneous fibroblasts. The diagnosis can be confirmed by identification of the gene mutations. Genetic analysis also allows screening of carrier females, who may have patches with cutaneous and hair anomalies, and prenatal diagnosis through chorionic villus sampling.Because MD is X-linked recessive, affected females are very rare. So far, only eight cases have been described in literature and cytogenetic studies have been reported only in five cases (Table 1): one displayed a mosaicism 45,X/46,XX and the remaining four showed a de novo balanced translocation between the chromosome X and an autosome. The breakpoint on the X chromosome is Xq13 where the gene ATP7A has been mapped.In this article, we describe a female with MD carrying a balanced translocation between the chromosomes X and 16 producing the disruption of one copy of ATP7A gene and silencing of the other copy. Moreover, the late-replicating chromosome X has been inve...

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“…The copper contents of cultured skin fibroblasts were analysed according to a previous report [11], however whole cells (instead of the supernatants of sonicated cell pellets) were used. The patients' fibroblasts, cultured in Eagles' minimum essential medium supplemented with 10% fetal calf serum, contained a copper level that was 1.5-fold that of the control.…”

Section: Copper Metabolismmentioning

confidence: 99%

Sibling cases of a degenerative neurological disease associated with hypocupraemia and hypobetalipoproteinaemia

et al. 1993

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We describe two siblings, a boy and his younger sister, with degenerative neurological disturbances, hypocupraemia and hypobetalipoproteinaemia. The neurological features in both cases were developmental delay, dysarthria, hyperkinetics with an attention deficit, dysdiadochokinesis, night blindness, myoclonic jerks and convulsions. Their serum cooper levels did not increase despite administration of copper sulphate both orally or intravenously. The copper contents of the cultured fibroblasts in the patients were 1.5-fold that of controls. Although neurological disorders associated with abnormal copper metabolism and inherited in an X-linked manner have been previously reported, this is the first report of a neurodegenerative disease concurrent with abnormal copper metabolism and hypobetalipoproteinaemia.

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Copper deficiency in the mitochondria of cultured skin fibroblasts from patients with menkes syndrome

Cited by 34 publications

References 12 publications

Histochemical localization of copper in the intestine and kidney of macular mice: light and electron microscopic study.

Histochemical localization of copper in the intestine and kidney of macular mice: light and electron microscopic study.

Lyonization Effects of the t(X;16) Translocation on the Phenotypic Expression in a Rare Female With Menkes Disease

Sibling cases of a degenerative neurological disease associated with hypocupraemia and hypobetalipoproteinaemia

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