Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.

Harris, Z L; Takahashi, Y; Miyajima, H; Serizawa, M; MacGillivray, R T; Gitlin, J D

doi:10.1073/pnas.92.7.2539

Cited by 558Neurological diseases and metabolismTrace Elements in HealthIron Metabolism and Disorders

Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.

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Harris, Z L, Takahashi, Y, Miyajima, H, Serizawa, M, MacGillivray, R T, Gitlin, J D·1995·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.92.7.2539PMC PMC42253

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Abstract

Ceruloplasmin is an abundant alpha 2-serum glycoprotein that contains 95% of the copper found in the plasma of vertebrate species. We report here on the identification of a genetic defect in the ceruloplasmin gene in a patient previously noted to have a total absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration. In this patient T2 (transverse relaxation time)-weighted magnetic resonance imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410, resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patient's daughter, which revealed heterozygosity for this same 5-bp insertion. The presence of this mutation in conjunction with the clinical and pathologic findings demonstrates an essential role for ceruloplasmin in human biology and identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism. These findings support previous studies that identified ceruloplasmin as a ferroxidase and are remarkably consistent with recent studies on the essential role of a homologous copper oxidase in iron metabolism in yeast. The clinical and laboratory findings suggest that additional patients with movement disorders and nonclassical Wilson disease should be examined for ceruloplasmin gene mutations.

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Iron deficiency in ceruloplasmin deficiency results from lack of ferroxidase activity needed to mobilize iron from storage.
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Background
Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders
Loeffler, D. A., LeWitt, P. A., Juneau, P. L., Sima, A. A. F., Nguyen, H.-U., DeMaggio, A. J., Brickman, C. M., Brewer, G. J., Dick, R. D., Troyer, M. D., et al. (1996) · Brain Research · doi:10.1016/s0006-8993(96)00782-2 · Cited by 237 · see citing works
Crystal structure of the Atx1 metallochaperone protein at 1.02 Å resolution
Rosenzweig, A. C., Huffman, D. L., Hou, M. Y., Wernimont, A. K., Pufahl, R. A., & O’Halloran, T. V. (1999) · Structure · doi:10.1016/s0969-2126(99)80082-3 · Cited by 236 · see citing works
Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders
Qian, Z., & Wang, Q. (1998) · Brain Research Reviews · doi:10.1016/s0165-0173(98)00012-5 · Cited by 230 · see citing works
Iron and copper transport in yeast and its relevance to human disease
Askwith, C. C., & Kaplan, J. (1998) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01192-x · Cited by 220 · see citing works
Iron Homeostasis in the Liver
Anderson, E. R., & Shah, Y. M. (2012) · Comprehensive physiology · doi:10.1002/cphy.c120016 · Cited by 249 · see citing works
The iron metabolism of neoplastic cells: Alterations that facilitate proliferation?
Kwok, J. C., & Richardson, D. R. (2002) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(01)00213-x · Cited by 215 · see citing works
Iron Metabolism: Iron Deficiency and Iron Overload
Andrews, N. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.75 · Cited by 209 · see citing works
Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities
Singh, N., Haldar, S., Tripathi, A. K., Horback, K., Wong, J., Sharma, D., Beserra, A., Suda, S., Anbalagan, C., Dev, S., et al. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4931 · Cited by 205 · see citing works
“NBIA disorders comprise two main syndromes: pantothe-nate kinase-associated neurodegeneration (PKAN) or NBIA type 1 comprising * 50% of all reported cases, and phospho-lipase A2-associated neurodegeneration (PLAN) or NBIA-type 2 (101, 190, 194).”
Multi-Copper Oxidases and Human Iron Metabolism
Vashchenko, G., & MacGillivray, R. T. A. (2013) · Nutrients · doi:10.3390/nu5072289 · Cited by 212 · see citing works
“Confirming the role of ceruloplasmin in iron export, aceruloplasminaemic patients develop massive accumulation of iron in various tissues, including the liver, pancreas and brain [72,116].”
Background
Alternative RNA Splicing Generates a Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin in Mammalian Brain
Patel, B. N., Dunn, R. J., & David, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.6.4305 · Cited by 202 · see citing works
Nitrosothiol Formation Catalyzed by Ceruloplasmin
Inoue, K., Akaike, T., Miyamoto, Y., Okamoto, T., Sawa, T., Otagiri, M., Suzuki, S., Yoshimura, T., & Maeda, H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.38.27069 · Cited by 200 · see citing works
Iron Regulation: Macrophages in Control
Sukhbaatar, N., & Weichhart, T. (2018) · Pharmaceuticals · doi:10.3390/ph11040137 · Cited by 201 · see citing works
Role of Ceruloplasmin in Cellular Iron Uptake
Mukhopadhyay, C. K., Attieh, Z. K., & Fox, P. L. (1998) · Science · doi:10.1126/science.279.5351.714 · Cited by 199 · see citing works
Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders
Camaschella, C. (2005) · Blood · doi:10.1182/blood-2005-05-1857 · Cited by 194 · see citing works
Ceruloplasmin gene expression in the murine central nervous system.
Klomp, L. W. J., Farhangrazi, Z. S., Dugan, L. L., & Gitlin, J. D. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118768 · Cited by 194 · see citing works
A Novel Gene Causing a Mendelian Audiogenic Mouse Epilepsy
Skradski, S. L., Clark, A. M., Jiang, H., White, H. S., Fu, Y., & Ptáček, L. J. (2001) · Neuron · doi:10.1016/s0896-6273(01)00397-x · Cited by 189 · see citing works
“A total of five litters were produced resulting in 29 BUB/ceruloplasmin in humans (Harris et al., 1995), have been BnJ and 11 SWR/Bm offspring.”
Method
Homeostatic Regulation of Copper Uptake in Yeast via Direct Binding of MAC1 Protein to Upstream Regulatory Sequences ofFRE1 and CTR1
Yamaguchi‐Iwai, Y., Serpe, M., Haile, D. J., Yang, W., Kosman, D. J., Klausner, R. D., & Dancis, A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.28.17711 · Cited by 187 · see citing works
Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation
Hartig, M., Hörtnagel, K., Garavaglia, B., Zorzi, G. S., Kmieć, T., Klopstock, T., Rostasy, K. M., Svetel, M. V., Kostić, V., Schuelke, M., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20771 · Cited by 183 · see citing works
Brain Iron Metabolism Dysfunction in Parkinson’s Disease
Jiang, H. F., Wang, J., Rogers, J. T., & Xie, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9879-1 · Cited by 183 · see citing works
The Copper-transporting ATPases, Menkes and Wilson Disease Proteins, Have Distinct Roles in Adult and Developing Cerebellum
Barnes, N. L., Tsivkovskii, R., Tsivkovskaia, N. O., & Lutsenko, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413840200 · Cited by 176 · see citing works
Ceruloplasmin and cardiovascular disease
Fox, P. L., Mazumder, B., Ehrenwald, E., & Mukhopadhyay, C. K. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00231-8 · Cited by 176 · see citing works
Use of desferrioxamine in the treatment of aceruloplasminemia
Miyajima, H., Takahashi, Y., Kamata, T., Shimizu, H., Sakai, N., & Gitlin, J. D. (1997) · Annals of Neurology · doi:10.1002/ana.410410318 · Cited by 173 · see citing works
The Crd1 gene encodes a putative di‐iron enzyme required for photosystem I accumulation in copper deficiency and hypoxia in Chlamydomonas reinhardtii
Moseley, J. L., Quinn, J. M., Eriksson, M., & Merchant, S. (2000) · The EMBO Journal · doi:10.1093/emboj/19.10.2139 · Cited by 174 · see citing works
Iron homeostasis: new tales from the crypt
Roy, C. N., & Enns, C. A. (2000) · Blood · doi:10.1182/blood.v96.13.4020 · Cited by 175 · see citing works
Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases
Boll, M.-C., Alcaraz-Zubeldia, M., Montes, S., & Rios, C. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9610-3 · Cited by 173 · see citing works
“Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the ceruloplasmin gene expressed in the CNS [20].”
BackgroundInfluential
Iron dysregulation in movement disorders
Dušek, P., Jankovic, J. J., & Le, W. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.054 · Cited by 172 · see citing works
A Systems Biology Approach to Iron Metabolism
Chifman, J., Laubenbacher, R., & Torti, S. V. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-2095-2_10 · Cited by 175 · see citing works
“Aceruloplasminemia—Aceruloplasminemia is a disorder caused by mutations in the gene encoding ceruloplasmin (Cp), a ferroxidase involved in the loading of Fe onto Tf following its release from cells [70,71].”
Background
Mechanisms of Copper Incorporation into Human Ceruloplasmin
Hellman, N. E., Kono, S., Mancini, G. M. S., Hoogeboom, A. J. M., de Jong, G. J., & Gitlin, J. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206246200 · Cited by 170 · see citing works
Genetic Defects in Copper Metabolism
Shim, H., & Harris, Z. L. (2003) · Journal of Nutrition · doi:10.1093/jn/133.5.1527s · Cited by 167 · see citing works
Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver
Doğuer, Ç., Ha, J., & Collins, J. F. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170045 · Cited by 214 · see citing works
Effect of copper deficiency on prenatal development and pregnancy outcome
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Restriction of Copper Export in Saccharomyces cerevisiae to a Late Golgi or Post-Golgi Compartment in the Secretory Pathway
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Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia
Klomp, L. W. J. (1996) · Human Molecular Genetics · doi:10.1093/hmg/5.12.1989 · Cited by 161 · see citing works
Aceruloplasminemia: An Inherited Neurodegenerative Disease with Impairment of Iron Homeostasis
XU, X., PIN, S., GATHINJI, M., FUCHS, R., & HARRIS, Z. L. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1306.024 · Cited by 160 · see citing works
Bacterial Mn2+Oxidizing Systems and Multicopper Oxidases: An Overview of Mechanisms and Functions
G. J. Brouwers, E. V. (2000) · Geomicrobiology Journal · doi:10.1080/014904500270459 · Cited by 159 · see citing works
“The human genetic disease aceruloplasminemia (absence of ceruloplasmin) results in defects in iron homeostasis, including iron accumulation in tissues (Harris et al. 1995).”
Background
Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy
McCarthy, R. C., & Kosman, D. J. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1771-4 · Cited by 158 · see citing works
“Aceruloplasminemia is an autosomal recessive disorder caused by loss-of-function mutations in the Cp gene [4, 172, 173].”
Iron Homeostasis: Recently Identified Proteins Provide Insight into Novel Control Mechanisms
Zhang, A.-S., & Enns, C. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.r800017200 · Cited by 153 · see citing works
Ceruloplasmin Is an Endogenous Inhibitor of Myeloperoxidase
Chapman, A., Mocatta, T. J., Shiva, S., Seidel, A., Chen, B., Khalilova, I. S., Paumann-Page, M., Jameson, G. N. L., Winterbourn, C. C., & Kettle, A. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.418970 · Cited by 153 · see citing works
“Aceruloplasminemia is a rare autosomal recessive disease that results in iron accumulation in the pancreas, liver, and brain, and patients suffer from diabetes and neurodegeneration (61).”
Background
Functional dissection of astrocyte-secreted proteins: Implications in brain health and diseases
Jha, M. K., Kim, J.-H., Song, G. J., Lee, W., Lee, I. K., Lee, H., An, S. S. A., Kim, S., & Suk, K. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.12.003 · Cited by 149 · see citing works
“A rare autosomal recessive disorder, aceruloplasminemia, which results from the loss of ceruloplasmin in serum and other tissues (Roberti Mdo et al., 2011), is characterized by impaired iron homeostasis (Harris et al., 1998, 1995).”
Background
Ceruloplasmin in neurodegenerative diseases
Vassiliev, V. B., Harris, Z. L., & Zatta, P. F. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2005.03.003 · Cited by 148 · see citing works
Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies
Ma, L., Azad, M. G., Dharmasivam, M., Richardson, V., Quinn, R. J., Feng, Y., Pountney, D. L., Tonissen, K. F., Mellick, G. D., Yanatori, I., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101896 · Cited by 148 · see citing works
“This includes work examining human aceruloplasminemia, where iron loading occurs in both neurons and glia of the striatum and dentate nucleus of the brain, the parenchymal cells of the liver, pancreas, heart, kidney, spleen and thyroid gland [193,194].”
Background
Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice
Jeong, S. Y., & David, S. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2922-06.2006 · Cited by 148 · see citing works
“Null mutations of the Cp gene in humans (aceruloplasminemia) result in iron accumulation in various organs including the liver and CNS (Harris et al., 1995; Morita et al., 1995; Yoshida et al., 1995).”
Background
Does oxidative stress change ceruloplasmin from a protective to a vasculopathic factor?
Shukla, N., Maher, J., Masters, J. M., Angelini, G. D., & Jeremy, J. Y. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2005.11.035 · Cited by 145 · see citing works
“[34] Harris ZL, Takahashi Y, Miyajima H, et al.”
Background
Basic and Clinical Aspects of Copper
Harris, E. D. (2003) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360390250649 · Cited by 154 · see citing works
Neurodegeneration with brain iron accumulation–clinical syndromes and neuroimaging
Schipper, H. M. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.06.016 · Cited by 141 · see citing works
Aceruloplasminemia
Gitlin, J. D. (1998) · Pediatric Research · doi:10.1203/00006450-199809000-00001 · Cited by 140 · see citing works
Binding and inhibition of myeloperoxidase (MPO): a major function of ceruloplasmin?
Segelmark, M., PERSSON, B., Hellmark, T., & Wieslander, J. (1997) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.1997.d01-992.x · Cited by 138 · see citing works
Aceruloplasminemia, an inherited disorder of iron metabolism
Miyajima, H., Takahashi, Y., & Kono, S. (2003) · BioMetals · doi:10.1023/a:1020775101654 · Cited by 136 · see citing works
“Table 4 shows a summary of mutations in the ceruloplasmin gene in aceruloplasminemia (Yoshida et al. 1995; Harris et al. 1995; Daimon et al. 1995; Takahashi et al. 1996; Okamoto et al. 1996; Harris et al. 1996; Yazaki et al. 1998; Miyajima et al. 1999; Kohno et al. 1999; Daimon et al. 2000; Hellman…”
BackgroundInfluential
The genetics of essential metal homeostasis during development
Kambe, T., Weaver, B. P., & Andrews, G. K. (2008) · genesis · doi:10.1002/dvg.20382 · Cited by 136 · see citing works
“In humans CP deficiency has been associated with late-onset retinal and basal ganglia degeneration (Harris et al., 1995) and increased iron accumulation in the liver and other tissues.”
Background
IRON TOXICITY AS A POTENTIAL FACTOR IN AMD
WONG, R. W., RICHA, D. C., HAHN, P., GREEN, W. R., & DUNAIEF, J. L. (2007) · Retina · doi:10.1097/iae.0b013e318074c290 · Cited by 131 · see citing works
Aceruloplasminemia, an iron metabolic disorder
Miyajima, H. (2003) · Neuropathology · doi:10.1046/j.1440-1789.2003.00521.x · Cited by 134 · see citing works
“Aceruloplasminemia is characterized by mutations in the ceruloplasmin gene itself.(5,6) Ceruloplasmin, a multicopper ferroxidase that affects the distribution of tissue iron, has antioxidant effects through the oxidation of ferrous iron to ferric iron.”
Background
Copper dyshomoeostasis in Parkinson's disease: implications for pathogenesis and indications for novel therapeutics
Davies, K. M., Mercer, J. F. B., Chen, N., & Double, K. L. (2016) · Clinical Science · doi:10.1042/cs20150153 · Cited by 134 · see citing works

Aceruloplasminemia
Gitlin, J. D. (1998) · Pediatric Research · doi:10.1203/00006450-199809000-00001 · Cited by 140 · see citing works
Aceruloplasminemia, an inherited disorder of iron metabolism
Miyajima, H., Takahashi, Y., & Kono, S. (2003) · BioMetals · doi:10.1023/a:1020775101654 · Cited by 136 · see citing works
The copper-iron connection: Hereditary aceruloplasminemia
Nittis, T., & Gitlin, J. D. (2002) · Seminars in Hematology · doi:10.1053/shem.2002.35633 · Cited by 73 · see citing works
Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis
Harris, Z. L., Klomp, L. W. J., & Gitlin, J. (1998) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/67.5.972s · Cited by 253 · see citing works
Characterization of a Nonsense Mutation in the Ceruloplasmin Gene Resulting in Diabetes and Neurodegenerative Disease
Takahashi, Y., Miyajima, H., Shirabe, S., Nagataki, S., Suenaga, A., & Gitlin, J. D. (1996) · Human Molecular Genetics · doi:10.1093/hmg/5.1.81 · Cited by 118 · see citing works

Authors: Harris, Z. L., Takahashi, Y., Miyajima, H., Serizawa, M., MacGillivray, R. T., & Gitlin, J. D.
Affiliations: Washington University in St. Louis (US)
ORCID: Harris, Z L
Miyajima, H
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1995-03-28
Volume: 92
Issue: 7
Pages: 2539-2543
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.92.7.2539
PMC: PMC42253
OpenAlex: W2132544275
Cited by: 558
References: 29
Citations by year: 2026: 3 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 15 · 2020: 9 · 2019: 12 · 2018: 17 · 2017: 10 · 2016: 13 · 2015: 16 · 2014: 16 · 2013: 22 · 2012: 20
FWCI: 16.77
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01hl041536-13)
National Heart, Lung, and Blood Institute (HL41536)
Topics: Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords: aceruloplasminemia, ceruloplasmin, frameshift mutation, iron metabolism, iron accumulation, basal ganglia degeneration, retinal degeneration, ferroxidase, copper oxidase, autosomal recessive disorder, movement disorders, heterozygosity
MeSH terms: Amino Acid Sequence, Animals, Basal Ganglia, Base Sequence, Blepharospasm, Ceruloplasmin, DNA, Exons, Female, Humans, Iron, Magnetic Resonance Imaging, Metal Metabolism, Inborn Errors, Middle Aged, Molecular Sequence Data, Reference Values, Retinal Degeneration, Vertebrates, Polymerase Chain Reaction, DNA Primers

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Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.

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