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Molecular Genetics and Metabolism Dec 2014Mottled-dappled (Mo-dp) is a mouse model of Menkes disease caused by a large, previously uncharacterized deletion in the 5' region of Atp7a, the mouse ortholog of ATP7A....
Mottled-dappled (Mo-dp) is a mouse model of Menkes disease caused by a large, previously uncharacterized deletion in the 5' region of Atp7a, the mouse ortholog of ATP7A. Affected mutants die in utero at embryonic day 17, and show bending and thickening of the ribs and distortion of the pectoral and pelvic girdles and limbs. To characterize this allele, we designed a custom 4x180K microarray on the mouse X chromosome and performed comparative genomic hybridization using extracted DNA from normal and carrier Mo-dp females, and identified an approximately 9 kb deletion. We used PCR to fine-map the breakpoints and amplify a junction fragment of 630 bp. Sequencing of the junction fragment disclosed the exact breakpoint locations and that the Mo-dp deletion is precisely 8990 bp, including approximately 2 kb in the promoter region of Atp7a. Western blot analysis of Mo-dp heterozygous brains showed diminished amounts of Atp7a protein, consistent with reduced expression due to the promoter region deletion on one allele. In heterozygous females, brain copper levels tended to be lower compared to wild type whereas neurochemical analyses revealed higher dihydroxyphenylacetic acid:dihydroxyphenylglycol (DOPAC:DHPG) and dopamine:norepinephrine (DA:NE) ratios compared to normal (P=0.002 and 0.029, respectively), consistent with partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. Heterozygous females showed no significant differences in body weight compared to wild type females. Our results delineate the molecular details of the Mo-dp mutation for the first time and define novel biochemical findings in heterozygous female carriers of this allele.
Topics: Adenosine Triphosphatases; Alleles; Animals; Blotting, Western; Body Weight; Brain; Cation Transport Proteins; Comparative Genomic Hybridization; Copper; Copper-Transporting ATPases; Disease Models, Animal; Dopamine beta-Hydroxylase; Female; Heterozygote; Humans; Menkes Kinky Hair Syndrome; Mice; Oligonucleotide Array Sequence Analysis; Phenotype; Polymerase Chain Reaction; Sequence Analysis, DNA; Sequence Deletion; X Chromosome
PubMed: 25456742
DOI: 10.1016/j.ymgme.2014.10.001 -
American Journal of Medical Genetics.... Feb 2015Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in... (Review)
Review
Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in the APT7A gene. In its classic form, it manifests in boys with hypotonia, seizures, skin and joint laxity, hair twisting (pili torti), cerebrovascular tortuosity, and bladder diverticulae. Menkes disease phenotypes have been reported in females with X; autosome translocations-disrupting ATP7A gene function- or ATP7A gene alterations. Those females manifest variable clinical findings, some of which, such as pili torti, seizure presence and/or age of onset, cerebrovascular tortuosity, degree of intellectual disability, and bladder divericulae are largely under-reported and under-studied. Here, we report on three females with Menkes disease and variant phenotypes, sharing characteristic features, one with classic Menkes disease and two with Menkes disease variants. We conclude that Menkes disease in females manifests with a variable spectrum of clinical findings but a few are uniformly present such as neurodevelopmental disability, hypotonia, and connective tissue findings. Others, such as seizures, cerebral atrophy, and cerebrovascular tortuosity may be present but are under-reported and under- studied. We propose that the diagnosis of Menkes disease or variants in females with suspicious clinical findings is an important one to consider as early treatment with parenteral copper may be considered. The effect of this treatment on the disease course in females with MD is unknown and remains to be seen.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Cerebral Angiography; Child; Child, Preschool; Copper-Transporting ATPases; Exons; Female; Heterozygote; Humans; Infant; Magnetic Resonance Angiography; Menkes Kinky Hair Syndrome; Mutation; Phenotype
PubMed: 25428120
DOI: 10.1002/ajmg.a.36853 -
Journal of Trace Elements in Medicine... Oct 2014Menkes disease is an X-linked recessive disorder of brain copper metabolism caused by mutations in an essential mammalian copper transport gene, ATP7A. Untreated...
Menkes disease is an X-linked recessive disorder of brain copper metabolism caused by mutations in an essential mammalian copper transport gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. Death by age three years is typical. While provision of working copies of ATP7A to the brain by viral vectors is a promising strategy under development, the only treatment currently available is subcutaneous copper injections. These can normalize circulating blood levels and may replete brain copper depending on the molecular context, e.g., the severity of ATP7A mutation and potential presence of mosaicism. In this paper, we summarize somatic growth and neurodevelopmental outcomes for 60 subjects enrolled in a recently concluded phase I/II clinical trial of copper histidine for Menkes disease (ClinicalTrials.gov Identifier: NCT00001262). Primary outcomes indicate highly statistically significant improvements in gross motor, fine motor/adaptive, personal-social, and language neurodevelopment in the cohort of subjects who received early treatment prior to onset of symptoms (n=35). Correlating with these findings, quantitative parameters of somatic growth indicated statistically significant greater growth in head circumference for the initially asymptomatic group, whereas weight and height/length at age three years (or at time of death) did not differ significantly. Mortality at age 3 was higher (50%) in subjects older and symptomatic when treatment commenced compared to the asymptomatic group (28.6%). We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation.
Topics: Adenosine Triphosphatases; Brain; Cation Transport Proteins; Child, Preschool; Copper; Copper-Transporting ATPases; Female; Humans; Male; Menkes Kinky Hair Syndrome; Mutation
PubMed: 25281031
DOI: 10.1016/j.jtemb.2014.08.008 -
PloS One 2014The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that...
The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb) from the circulation, as well as the induction of haem oxygenase 1 (HO1) in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Cell Line; Copper; Copper-Transporting ATPases; Disease Models, Animal; Erythrocytes; Female; Gene Expression Regulation; Heme Oxygenase-1; Hemolysis; Hepcidins; Humans; Iron; Kidney; Liver; Male; Membrane Proteins; Menkes Kinky Hair Syndrome; Mice; Mutation; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 25247420
DOI: 10.1371/journal.pone.0107641 -
Biometals : An International Journal on... Aug 2014Copper (Cu) is an essential microelement found in all living organisms with the unique ability to adopt two different redox states-in the oxidized (Cu(2+)) and reduced... (Review)
Review
Copper (Cu) is an essential microelement found in all living organisms with the unique ability to adopt two different redox states-in the oxidized (Cu(2+)) and reduced (Cu(+)). It is required for survival and serves as an important catalytic cofactor in redox chemistry for proteins that carry out fundamental biological functions, important in growth and development. The deficit of copper can result in impaired energy production, abnormal glucose and cholesterol metabolism, increased oxidative damage, increased tissue iron (Fe) accrual, altered structure and function of circulating blood and immune cells, abnormal neuropeptides synthesis and processing, aberrant cardiac electrophysiology, impaired myocardial contractility, and persistent effects on the neurobehavioral and the immune system. Increased copper level has been found in several disorders like e.g.: Wilson's disease or Menke's disease. New findings with the great potential for impact in medicine include the use of copper-lowering therapy for antiangiogenesis, antifibrotic and anti-inflammatory purposes. The role of copper in formation of amyloid plaques in Alzheimer's disease, and successful treatment of this disorder in rodent model by copper chelating are also of interest. In this work we will try to describe essential aspects of copper in chosen diseases. We will represent the evidence available on adverse effect derived from copper deficiency and copper excess. We will try to review also the copper biomarkers (chosen enzymes) that help reflect the level of copper in the body.
Topics: Alzheimer Disease; Animals; Copper; Environmental Pollutants; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Metalloproteins; Oxidation-Reduction; Oxidative Stress
PubMed: 24748564
DOI: 10.1007/s10534-014-9736-5