Functional copper transport explains neurologic sparing in Occipital Horn syndrome

Tang, Jingrong; Robertson, Stephen P.; Lem, Kristen; Godwin, Sarah C.; Kaler, Stephen G.

doi:10.1097/01.gim.0000245578.94312.1e

Cited by 55 publications

(70 citation statements)

References 39 publications

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“…22 Other mutant constructs were prepared in the same fashion, and DNA cassettes containing sequences of interest were ligated into a yeast expression vector, MNKpYES6/CT, with fidelity confirmed by sequencing. We used wild-type and ccc2 deletion (CCC2 copper-transport deletion 23 ) strains of Saccharomyces cerevisiae; the ccc2 deletion strain was from the Saccharomyces Genome Deletion Project.…”

Section: Yeast Complementation Assaymentioning

confidence: 99%

“…24 Transformation of ccc2 deletion and complementation experiments were performed as previously described. 22 …”

Section: Yeast Complementation Assaymentioning

confidence: 99%

“…We used a yeast complementation assay 22 to study the effects of deletion of exons 20 to 23 and G666R on ATP7A function. The results indicated that G666R partially complemented the S. cerevisiae copper-transport knockout ccc2 deletion, indicating some residual functional copper-transport capacity in this mutant allele (Fig.…”

Section: Characterization Of Mutationsmentioning

confidence: 99%

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Neonatal Diagnosis and Treatment of Menkes Disease

Kaler¹,

Holmes²,

Goldstein³

et al. 2008

N Engl J Med

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Section: Yeast Complementation Assaymentioning

confidence: 99%

“…24 Transformation of ccc2 deletion and complementation experiments were performed as previously described. 22 …”

Section: Yeast Complementation Assaymentioning

confidence: 99%

Section: Characterization Of Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Neonatal Diagnosis and Treatment of Menkes Disease

Kaler¹,

Holmes²,

Goldstein³

et al. 2008

N Engl J Med

Self Cite

275

291

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show abstract

“…Patients with OHS, a milder form of Menkes disease, also exhibit connective tissue impairments but are spared of severe neurological abnormalities, presumably owing to residual expression of functional ATP7A (Das et al, 1995;Mercer, 1998;Møller et al, 2000;Tang et al, 2006;Tsukahara et al, 1994). The mottled mutant mice are a series of copper-deficient mice that possess mutations in the murine homologue of the Menkes disease gene; these mutants display a diversity of phenotypic severities ranging from prenatal lethality to an adult viable phenotype (Kim and Petris, 2007;La Fontaine et al, 1999;Llanos et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A Drosophila model of Menkes disease reveals a role for DmATP7 in copper absorption and neurodevelopment

Bahadorani

Marcon

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARY Human Menkes disease is a lethal neurodegenerative disorder of copper metabolism that is caused by mutations in the ATP7A copper-transporting gene. In the present study, we attempted to construct a Drosophila model of Menkes disease by RNA interference (RNAi)-induced silencing of DmATP7, the Drosophila orthologue of mammalian ATP7A, in the digestive tract. Here, we show that a lowered level of DmATP7 mRNA in the digestive tract results in a reduced copper content in the head and the rest of the body of surviving adults, presumably owing to copper entrapment in the gut. Similar to Menkes patients, a majority of flies exhibit an impaired neurological development during metamorphosis and die before eclosion. In addition, we show that survival to the adult stage is highly dependent on the copper content of the food and that overexpression of the copper homeostasis gene, metal-responsive transcription factor-1 (MTF-1), enhances survival to the adulthood stage. Taken together, these results highlight the role of DmATP7-mediated copper uptake in the neurodevelopment of Drosophila melanogaster and provide a framework for the analysis of potential gene interactions influencing Menkes disease.

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“…Menkes patients exhibit symptoms consistent with hypoactivity of copper-dependent enzymes, including severe mental retardation associated with neurodegeneration and seizures, reduced melanin pigmentation, and impaired extracellular matrix formation. Mutations in ATP7A can also manifest as occipital horn syndrome, a connective tissue disorder arising from copper deficiency in which patients are spared the neurological symptoms of Menkes disease (31). More recently, certain partial loss-of-function mutations in ATP7A were shown to cause a distal motor neuropathy known as X-linked spinal muscular atrophy type 3 (SMAX3) (13,39).…”

mentioning

confidence: 99%

Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein

Wang

Zhu

Hodgkinson

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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The essential requirement for copper in early development is dramatically illustrated by Menkes disease, a fatal neurodegenerative disorder of early childhood caused by loss-of-function mutations in the gene encoding the copper transporting ATPase ATP7A. In this study, we generated mice with enterocyte-specific knockout of the murine ATP7A gene ( Atp7a) to test its importance in dietary copper acquisition. Although mice lacking Atp7a protein within intestinal enterocytes appeared normal at birth, they exhibited profound growth impairment and neurological deterioration as a consequence of copper deficiency, resulting in excessive mortality prior to weaning. Copper supplementation of lactating females or parenteral copper injection of the affected offspring markedly attenuated this rapid demise. Enterocyte-specific deletion of Atp7a in rescued pregnant females did not restrict embryogenesis; however, copper accumulation in the late-term fetus was severely reduced, resulting in early postnatal mortality. Taken together, these data demonstrate unique and specific requirements for enterocyte Atp7a in neonatal and maternofetal copper acquisition that are dependent on dietary copper availability, thus providing new insights into the mechanisms of gene-nutrient interaction essential for early human development.

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Functional copper transport explains neurologic sparing in Occipital Horn syndrome

Cited by 55 publications

References 39 publications

Neonatal Diagnosis and Treatment of Menkes Disease

Neonatal Diagnosis and Treatment of Menkes Disease

A Drosophila model of Menkes disease reveals a role for DmATP7 in copper absorption and neurodevelopment

Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein

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