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Genetic Determinants of Trace Element Metabolism

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Genetic Determinants of Trace Element Metabolism ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 29, No. .1 Copyright © 1999, Institute for Clinical Science, Inc. Genetic Determinants of Trace Element Metabolism DOUGLAS M. TEMPLETON, Ph.D., M.D. Department of Laboratory Medicine and Pathobiology, Faculty o f Medicine, University o f Toronto, Toronto M5G 1L5, Canada. The final years of the millennium have wit­ similar copper transporters, yet whereas Men­ nessed a breakthrough in our understanding of kes is a disease of copper deficiency presenting a number of metal-related disease processes as in infancy, Wilson disease is one of copper the responsible genes and their corresponding overload generally developing later in adult­ proteins have been identified. These events hood. Both are characterized by decreased lev­ have paralleled, and no doubt contributed to, a els of ceruloplasmin. change of perspective in metallobiochemistiy. Whereas the metal ion was formerly the focus M e n k e s D is e a s e of attention, today we tend to think first about the proteins that permissively or actively gov­ Menkes disease is a syndrome of abnormal ern the trafficking and utilization of the ion. neurodevelopment which runs a natural The chemistry of the metal, once the focus of course of developmental regression, seizures, the bioinorganic chemist, has taken second and death in infancy or early childhood. It place to the molecular biology of the metal occurs as an X-linked disorder with an inci­ ion’s transporters, channels and chaperones. dence of between 1/100,000 and 1/250,000 live The result has been insight into metal-related births.8,9 It was recognized by Danks10 to diseases, as distinct from metal toxicology. Per­ result from copper deficiency and a genetic haps topping the list of successes in under­ defect in copper transport was suspected. The standing such diseases are the cloning of the responsible gene was identified by positional Menkes disease gene in 1993,1,2>3 the Wilson cloning by three groups in 1993.1>2'3 The gene, disease gene in 1993,4,5,6 and the gene for named ATP7A, includes a coding region of hereditary haemochromatosis in 1996.7 This 8.5 kb with nearly 4 kb of 3' untranslated overview will thus address mainly genetic dis­ sequence. It encodes a 1500-amino acid mem­ orders of iron and copper metabolism, but will ber of the P-type ATPase transporter family. It also have a few words to say about our pros­ is arranged in 23 exons spanning 150 kb of pects of recognizing genetic determinants of genomic DNA.11 In about 20% of cases dele­ other metal-related pathologies in the future. tions or rearrangements are found that are large enough to detect by Southern blot. Symptomatic point mutations occur through­ Copper out the sequence, but are clustered in exon 8, a region coding the stalk that connects the Wilson and Menkes diseases illustrate the metal-binding N-terminal to the remainder of extent of phenotypic divergence that can arise the protein.12 from closely related genetic determinants. The ATP7A protein has cystosolic N- and Both result from mutations in structurally C-terminal domains and eight intervening trans­ 24 0091-7370/99/0100-0024 $00.00 © Institute for Clinical Science, Inc. GENETIC DETERMINANTS OF TRACE ELEMENT METABOLISM 25 membrane regions. It has four signature ATP7B encodes a 1411-amino acid protein domains of the P-type ATPases13,14 that with an identical domain structure to the prod­ include a phosphatase domain (Thr-Gly-Glu- uct of ATP7A, ie, six copper-binding sites in Ala), a Cys-Pro-Cys domain in the putative cat­ the N-terminus, eight transmembrane regions, ion channel, and a conserved Asp residue and a phosphatase domain, a Cys-Pro-Cys domain ATP-binding domain in the cytosolic loop in the ion channel, and an Asp residue and between transmembrane regions 6 and 7. The ATP-binding domain in the cytosolic loop Asp residue is phosphorylated and subse­ between transmembrane regions 6 and 7. The quently dephosphorylated by the phosphatase gene spans over 80 kb of genomic DNA. In domain to effect a conformational change dur­ contrast to the large deletions found in ing the transport cycle. In the large cytosolic ATP7A, Wilson disease is associated only with N-terminal domain are found six copies of point mutations or small deletions.13 The Cys-X-X-Cys sequence that appear to be cop- mutation Hisl069Glu accounts for 38 per­ per-binding sites. They may serve to deliver cent of cases, but more than half the mutations copper to the transport machinery, or to main­ are rare.18 tain copper in the cuprous state to facilitate Recent evidence suggests that ATP- transport. Alternatively, a role in sensing cop­ independent transport of copper as Cu(I) per levels has been proposed (c/15). If three or occurs on the plasma membrane whereas the more of these metal-binding sites are lacking, ATP7B gene product transports Cu(II) in an the protein is non-functional.14 Various cul­ ATP-dependent manner and is located on the tured cells not expressing ATP7A take up cop­ Golgi membrane.15 This is consistent with a per at rates comparable to other cells but show role in incorporation of copper into ceruloplas­ delayed rates of copper efflux after copper min and is analogous to the iron transport sys­ loading.16 ATP7A is expressed in most cells tem of Saccharomyces cerevisiae, in which the except liver. The copper-deficient phenotype ATP-dependent copper transporter pumps in Menkes is explained by failure of the intes­ copper into an intracellular organelle for incor­ tinal epithelium to release absorbed dietary poration into the multicopper ferrooxidase, copper into the blood. FET3, required for iron acquisition by the cell.19 This is consistent with a role for ceru­ loplasmin in iron transport, as demonstrated W il s o n D is e a se by the aceruloplasminemic phenotype (see below) and explains the low levels of cerulo­ Dr. S. A. K. Wilson identified a syndrome plasmin generally observed in Wilson disease. of hepatolenticular degeneration in 1912.17 In cultured liver cells, increasing copper in the Typically, adults present with hepatic and medium caused the ATP7B protein to redis­ (or) neurological dysfunction secondary to tribute to a cytosolic vesicular compartment.20 copper accumulation, and may have asymp­ This is in contrast to the Menkes ATP7A pro­ tomatic Kayser-Fleischer rings reflecting tein, where increasing copper causes translo­ copper deposition in the cornea. World­ cation from the Golgi to the plasma mem­ wide, the disease affects about 30 people per brane.21 The cytosolic location is necessary for million population. The absence of ATP7A ceruloplasmin synthesis and for copper export. expression in liver suggested that a homolo­ There is also evidence that cleavage of about gous but unique protein might be expressed 20 kDa of the ATP7B N-terminal copper- there, perhaps reflecting the role of liver in binding region results in localization to the exercising homeostatic control over copper mitochondrion, suggesting a role in mitochon­ through biliary excretion. This suggested in drial copper homeostasis.22 An alternatively turn homology cloning strategies to identify spliced form of the protein lacking the regions the gene causing Wilson disease, and in 1993 coded by exons 6, 7, 8 and 12 is expressed in ATP7B was identified.4’5,6 the brain, where it localizes to cytosol.23 26 TEMPLETON This complex functional regulation suggests some initial concern that it represented an arti­ that mutations affecting protein trafficking, fact of the linkage disequilibrium strategy by post-translational modification or alternative which it had been located. splicing could all occur in addition to loss-of- It was known that presentation of various function mutations. Their future identification MHC class I molecules on the cell surface may help to explain the clinical variability of required expression of (32-microglobulin. This the disease. suggested that investigating iron metabolism in P2-microglobulin-deficient mice might shed Iron light on the role of HFE in HH and, indeed, |32-microglobulin-nuIl mice recapitulated the H aemochromatosis pathology of iron overload in H H .25 Intestinal mucosal iron uptake involves exposure of the Hereditary or idiopathic haemochromatosis epithelium to both redox states of iron in a (HH) is one of the most common genetic dis­ number of inorganic, organic and macro- eases, although a marked variability in the molecular species. Indiscriminate uptake degree of penetrance means the true inci­ of iron could still allow intracellular chemistry dence is unknown. Perhaps a good estimate in to control release to the plasma, or elimina­ the Caucasian population is 1/400, with a car­ tion through desquamation of the epithelia, so rier frequency proposed as high as one in release might be a more logical point of ten.24 The disease has long been known to control than uptake. As this reasoning would result from an inability to limit intestinal predict, the (32-microglobulin-null mice fail absorption of iron in response to replete iron to regulate release of iron from the intesti­ stores, and in its severest manifestations HH is nal epithelium.25 characterized by cirrhosis and hepatocellular The role of fi2-microglobulin is becoming carcinoma, cardiomyopathy and insulin- clearer. Mutant Cys282Tyr HFE protein fails dependent diabetes mellitus, each the conse­ to bind |32-microglobulin, does not translocate quence of iron overload in the respective to the cell surface and becomes prematurely organ. The paradoxically high prevalence of degraded in the Golgi.26,27 As in cystic fibrosis HH may indicate that enhanced absorption of and the cystic fibrosis transmembrane con­ iron has afforded an evolutionary advantage, ductance regulator, the most common muta­ particularly in women.
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