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Copper in Drinking Water (2000) / Chapter Skim
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4 Disorders of Copper Homeostasis
Pages 51-77

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From page 51...
... Occipital horn syndrome, a milder form of Menkes disease, is then discussed. Aceruloplasminemia, a newly recognized disease caused by a defect in the gene encoding ceruloplasmin, is then discussed.
From page 52...
... The primary genetic defect in Menkes disease is in the protein ATP7A, a membrane-bound Cu-ATPase that regulates the outward flow of copper ions from the interior to the exterior of the cell (Chelly et al. 1993; Mercer et al.
From page 53...
... 1993~. Spontaneous mutations at the mottled locus cause reduced fertility and viability and lead to phenotypic symptoms of classical Menkes disease and occipital horn syndrome (OHS)
From page 54...
... 1996~. Whereas the prevalence rate of Menkes disease appears to be 1 in 100,000-250,000 births, the prevalence rate of OHS appears to be much less.
From page 55...
... The observation might explain why OHS is a considered a mild as opposed to a debilitating form of Menkes disease. Tissues from mottled mutants bearing the blotchy allele display two large sized mRNAs, demonstrating a likely defect in splicing Fiercer et al.
From page 56...
... 1998~. GEN ETIC CHARACTERISTICS OF WILSON AND MENKES DISEASES The genetic mutations responsible for the loss of copper homeostasis are well characterized for Menkes and Wilson diseases.
From page 57...
... 1993~. A number of mutations can result in Menkes disease.
From page 58...
... H ETEROZYGOTES FOR WILSON DISEASE Because Wilson disease is an autosomal recessive disorder, it is exhibited only in individuals who are homozygous or compound heterozygotes1 for the gene defect. However, if the phenotype due to defects in the Wilson gene is defined as abnormal copper metabolism, then the Wilson gene can be considered a codominant gene, as abnormalities in copper homeostasis often occur in heterozygous carriers (Yuzbasiyan-Gurkan et al.
From page 59...
... Increased hepatic copper concentrations, which again approach the diagnostic concentration for Wilson disease, in siblings of Wilson patients (200 Gig of dry weight) (see Figure 4-2)
From page 60...
... 60 ~ in o a' ._ ~ _ ._ 5 ~ __ _ ~ ~ I_ 1\ 1~ Cal o oo CO ~ s~erqnS Jo ~0qtUnN CO Cal UP - ~)
From page 61...
... 61 Cal to o ~ In ·- a)
From page 62...
... Reprinted with permission from Medicine; copyright 1992, Lippincott Williams & Wilkins. ACERULOP~SMINEMIA Aceruloplasminemia is an autosomal recessive disorder of iron metabolism characterized by a defect in the gene coding for ceruToplasmin.
From page 63...
... 1998~. Tissue copper concentrations, however, tend to be unchanged and total iron-binding capacity and erythrocyte counts are normal.59Fe administered as a trace dose tends to accumulate in the brain, heart, kidney, and liver of patients with aceruloplasminemia, confirming the biopsy reports.
From page 64...
... 19961. The pathology of TIC is indistinguishable from Indian childhood cirrhosis and other forms of hepatic copper toxicosis (see descriptions below)
From page 65...
... (1998) hypothesized that ICT is caused by a combination of an autosomal recessive inherited defect in copper metabolism and excess copper intake.
From page 66...
... DISEASE-INDUCED CHANGES IN COPPER HOMEOSTASIS In addition to the above genetic disorders, there are a number of environmental and physiological conditions that can perturb copper metabolism and alter the delivery of copper to select tissues. The conditions shown to alter copper metabolism are diverse and include exercise, infection, inflammation, cirrhosis, diabetes, and hypertension (Sandstead 1995; Disilvestro et al.
From page 67...
... However, if persistent hypercupremia results in an increased excretion of copper, this condition might result in an increased dietary requirement for copper. CONCLUSIONS Menkes disease is X linked, and Wilson disease is an autosomal recessive disorder.
From page 68...
... The influence of heterozygosity for gene defects that alter copper transport or susceptibility to copper toxicity needs to be defined. Research should be conducted to establish the genetic causes of susceptibility to copper in TIC, ICC and ICT and the frequency of these genetic defects.
From page 69...
... 1994. Indian childhood cirrhosis-like liver disease in an Arab child.
From page 70...
... 1993. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.
From page 71...
... 1995. Molecular structure of the Menkes disease gene (ATP7A)
From page 72...
... 1992. Menkes disease: An X-linked neurological disorder of the copper metabolism.
From page 73...
... 1993. Isolation of a partial candidate gene for Menkes disease by positional cloning.
From page 74...
... 1996. Distinctive Menkes disease variant with occipital horns: delineation of natural history and clinical nh~not.vn~ Am ,T M~H (~T~n~t R.~('~ /' /l .~l Qi, M., and P.H.
From page 75...
... 1998. Copper efflux from murine microvascular cells requires expression of the Menkes disease Cu-ATPase.
From page 76...
... 1993. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.
From page 77...
... 1993. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson's disease.


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