Alternative titles; symbols
HGNC Approved Gene Symbol: CP
SNOMEDCT: 124224004;
Cytogenetic location: 3q24-q25.1 Genomic coordinates (GRCh38): 3:149,162,414-149,221,829 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q24-q25.1 | Aceruloplasminemia | 604290 | Autosomal recessive | 3 |
The CP gene encodes ceruloplasmin (also known as ferroxidase; iron (II):oxygen oxidoreductase, EC 1.16.3.1), a blue alpha-2-glycoprotein that binds 90 to 95% of plasma copper and has 6 or 7 cupric ions per molecule. It is involved in peroxidation of Fe(II) transferrin to form Fe(III) transferrin. Like transferrin (TF; 190000), ceruloplasmin is a plasma metalloprotein (Takahashi et al., 1984). CP is a plasma membrane glycoprotein that acts as a ferroxidase to facilitate ferroportin (SLC40A1; 604653)-mediated cellular iron export (summary by Di Meo and Tiranti, 2018).
Human ceruloplasmin is composed of a single polypeptide chain of 1,046 amino acids, with a molecular mass of 132 kD (Takahashi et al., 1984). Koschinsky et al. (1986) reported the nucleotide sequence of human preceruloplasmin cDNA. The mRNA from human liver was found to be 3,700 nucleotides in size. Sequence homology with factor VIII was demonstrated. The protein is synthesized in hepatocytes and secreted into the serum with copper incorporated during biosynthesis. Failure to incorporate copper during synthesis results in the secretion of an apoprotein devoid of copper, termed apoceruloplasmin (Culotta and Gitlin, 2001).
Yang et al. (1990) demonstrated 2 forms of CP which differed by the presence or absence of 12 nucleotide bases encoding a deduced sequence of gly-glu-tyr-pro in the C-terminal region of the molecule. Alternative splicing was the apparent explanation, and differential expression of the 2 transcripts in different tissues with production of isoforms from a single gene was demonstrated.
Klomp and Gitlin (1996) analyzed ceruloplasmin gene expression in the brain. In situ hybridization utilizing ceruloplasmin cDNA clones revealed abundant expression in specific populations of glial cells within the brain microvasculature, surrounding dopaminergic melanized neurons in the substantia nigra, and within the inner nuclear layer of the retina.
Di Meo and Tiranti (2018) stated that CP is the only known ferroxidase expressed by astrocytes.
Daimon et al. (1995) determined that the ceruloplasmin gene contains 19 exons and spans approximately 50 kb.
Klomp and Gitlin (1996) concluded that glial cell-specific ceruloplasmin gene expression is essential for iron homeostasis and neuronal survival in the human central nervous system.
Individuals with hereditary ceruloplasmin deficiency have profound iron accumulation in most tissues, suggesting that ceruloplasmin is important for normal release of cellular iron (Mukhopadhyay et al., 1998).
Weitkamp (1983) found a peak lod score of 3.5 at theta about 0.15 for linkage of CP to TF, which is located at 3q21. Homology argues for this linkage; TF and CP are linked in cattle with a lod score of 11.3 at 20% recombination frequency in sires (Larsen, 1977). By Southern blot analysis of human-mouse somatic cell hybrids, Naylor et al. (1985) mapped the CP gene to chromosome 3. Royle et al. (1987) localized the CP gene to 3q21-q24 by analysis of somatic cell hybrid DNAs and in situ hybridization.
Riddell et al. (1987) identified a ceruloplasmin pseudogene on chromosome 8. Koschinsky et al. (1987) isolated a processed gene for human ceruloplasmin and mapped it to chromosome 8 by somatic cell hybridization. Wang et al. (1988) localized the processed pseudogene further to 8q21.13-q23.1 by in situ hybridization. They pointed out that like all other processed pseudogenes described to date, the gene is located on a chromosome different from the parent gene.
Shreffler et al. (1967) identified at least 3 CP variants determined by codominant alleles by starch gel electrophoresis. Mohrenweiser and Decker (1982) identified several more electrophoretic variants of ceruloplasmin.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Aceruloplasminemia
In a Japanese woman with aceruloplasminemia (ACEP; 604290), originally reported by Miyajima et al. (1987), Harris et al. (1995) identified a homozygous frameshift mutation in the CP gene (117700.0002), resulting in a truncated open reading frame after 445 amino acids. The patient's asymptomatic daughter, who had a 50% decrease in ceruloplasmin levels, was heterozygous for the mutation.
In affected members of a Japanese family with ACEP reported by Morita et al. (1995), Yoshida et al. (1995) demonstrated a homozygous splice site mutation in the ceruloplasmin gene (117700.0001).
In a 45-year-old Japanese woman, born of consanguineous parents, with ACEP, Takahashi et al. (1996) identified a homozygous nonsense mutation in the CP gene (W858X; 117700.0003). The patient's younger brother, who had diabetes and retinal degeneration without other neurologic deficits, was also homozygous for the mutation.
In the 2 brothers with ACEP reported by Logan et al. (1994), Harris et al. (1996) found homozygosity for a 1-bp deletion (c.2389delG) in exon 13 of the CP gene (117700.0004). The nucleotide sequence surrounded this deletion site (TGGAGA) corresponded to a consensus sequence 'hotspot' for nucleotide deletions (Krawczak and Cooper, 1991). The nucleotide deletion resulted in a frameshift with change of 11 amino acids and a premature stop codon at codon 789.
In a 56-year-old Japanese man, born of consanguineous parents, with ACEP, Okamoto et al. (1996) identified a homozygous frameshift mutation in the CP gene (117700.0005).
In 12 individuals from 10 non-Japanese families with ACEP, Vila Cuenca et al. (2020) identified homozygous or compound heterozygous mutations in the CP gene (see, e.g., 117700.0006). There were 6 missense, 3 frameshifts, and 3 splice site mutations. An additional patient (a 40-year-old Polish woman, family 5) carried a heterozygous H130P variant; the authors noted that they could not exclude the presence of an additional CP mutation. Functional studies of the variants and studies of patient cells were not performed.
Internal duplication is a method of evolution of the genome illustrated by ceruloplasmin (Dwulet and Putnam, 1981). From internal homology of amino acid structure, Takahashi et al. (1983) concluded that the ceruloplasmin molecule evolved by tandem triplication of ancestral genes. From a computer search of the protein and nucleic acid sequence data banks of the National Biomedical Research Foundation, Church et al. (1984) found evidence that factor V (612309), factor VIII (300841), and ceruloplasmin may have had a common evolutionary origin.
To elucidate the role of ceruloplasmin in iron homeostasis, Harris et al. (1999) created an animal model of aceruloplasminemia by disrupting the murine Cp gene. Although normal at birth, Cp -/- mice demonstrated progressive accumulation of iron such that by 1 year of age all animals had a prominent elevation of serum keratin and a 3- to 6-fold increase in the iron content of the liver and spleen. Histologic analysis of affected tissues in these mice showed abundant iron stores within reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp +/+ and Cp -/- mice revealed equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp -/- mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. The findings demonstrated an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.
Mechanisms of brain and retinal iron homeostasis became subjects of increased interest after the discovery of elevated iron levels in brains of patients with Alzheimer disease (104300) and retinas of patients with age-related macular degeneration (603075). To determine whether Cp and its homolog hephestin (HEPH; 300167) are important for retinal iron homeostasis, Hahn et al. (2004) studied retinas from mice deficient in ceruloplasmin and/or hephestin. In normal mice, Cp and Heph localized to Muller glia and retinal pigment epithelium, a blood-brain barrier. Mice deficient in both Cp and Heph, but not each individually, had a striking, age-dependent increase in iron of the retinal pigment epithelium and retina. The iron storage protein ferritin (see 134790) was also increased in the doubly null retinas. After retinal iron levels had increased, mice null for both Cp and Heph had age-dependent retinal pigment epithelium hypertrophy, hypoplasia, and death, photoreceptor degeneration, and subretinal neovascularization, providing a model of some features of the human retinal diseases aceruloplasminemia and age-related macular degeneration. These pathologic changes indicated that ceruloplasmin and hephestin are critical for central nervous system iron homeostasis and that loss of both in the mouse leads to age-dependent retinal neurodegeneration, providing a model that can be used to test therapeutic efficacy of iron chelators and antiangiogenic agents.
Stasi et al. (2007) found that Cp mRNA and Cp protein were upregulated in the retinas of glaucomatous DBA/2 mice. Upregulation of Cp occurred at approximately the time of extensive retinal ganglion cell (RGC) death and increased with increasing age in the retinas but not in the brains of the animals. No age-related Cp upregulation was detected in the reference normal mouse strain (C57BL/6), which could develop significant nonglaucomatous RGC loss toward the end of the same time frame. Cp upregulation was also detected in most eyes from patients with glaucoma. Cp upregulation was localized to the Muller cells within the retinas and in the area of the inner limiting membrane. Stasi et al. (2007) concluded that the timing of this upregulation suggested that it may represent a reactive change of the retina in response to a noxious stimulus or to RGC death. Stasi et al. (2007) hypothesized that such Cp upregulation might represent a protective mechanism within the retina.
In a family with hypo- or aceruloplasminemia (604290) reported by Morita et al. (1995), Yoshida et al. (1995) demonstrated a G-to-A transition at the splice acceptor site, converting the canonical AG to AA immediately before the exon beginning with nucleotide 3019 of the cDNA. The parents were first cousins, thus indicating autosomal recessive inheritance, which was supported by the demonstration of homozygosity in the affected sibs. In this disorder, there is no copper overload. One of the 4 aceruloplasmic sibs was free of neurologic symptoms although he showed iron deposition. The proband from whom information on the distribution of iron deposits in the brain, liver, pancreas, heart, kidney, spleen, and thyroid gland was obtained had died at the age of 60 years, having shown dementia in the advanced stages of his disorder.
In a Japanese woman with aceruloplasminemia (ACEP; 604290) previously reported by Miyajima et al. (1987), Harris et al. (1995) identified a homozygous 5-bp insertion in the CP gene. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the CP gene revealed a size difference in exon 7. Sequencing of this exon uncovered a 5-bp insertion at amino acid 410, resulting in a frameshift mutation and a truncated open reading frame after 445 amino acids. The patient's asymptomatic daughter, who had a 50% decrease in ceruloplasmin levels, was heterozygous for mutation. The patient was a Japanese woman, 61 years old at the time of study, who had had retinal degeneration and blepharospasm for the previous 10 years. She had also developed cogwheel rigidity and dysarthria. Her younger sister, who was asymptomatic at the time of the original presentation despite undetectable CP, was 51 years old and had recent onset of retinal degeneration and basal ganglia symptoms. In each case, the absence of serum CP was associated with mild anemia, low serum iron, and elevated serum ferritin. Magnetic resonance imaging studies demonstrated changes in the basal ganglia suggestive of elevated iron content in the brain. Liver biopsy confirmed the presence of excess iron. The study by Harris et al. (1995) demonstrated the essential role of ceruloplasmin in human biology and identified aceruloplasminemia as an autosomal recessive disorder of iron metabolism. The findings supported previous studies that identified ceruloplasmin as a ferroxidase (Osaki et al., 1966) with a role in the ferric iron uptake by transferrin. Consistent with this concept, the anemia that develops in copper-deficient animals is unresponsive to iron but is correctable by ceruloplasmin administration (Lee et al., 1968). It is also consistent with the essential role of a homologous copper oxidase in iron metabolism in yeast.
In a 45-year-old Japanese woman, born of consanguineous parents, with aceruloplasminemia (ACEP; 604290), Takahashi et al. (1996) identified a homozygous G-to-A transition in exon 15 of the CP gene, resulting in a trp858-to-ter (W858X) substitution. The patient's younger brother, who had diabetes and retinal degeneration without other neurologic deficits, was also homozygous for the mutation. The proband was a 45-year-old woman who came to attention after a several-month history of difficulty in walking and slurring of speech. She had previously been in excellent health with the exception of insulin-dependent diabetes mellitus beginning at age 31 years. Physical examination revealed ataxic gait, scanning speech, and retinal degeneration. MRI of the brain was consistent with increased basal ganglia iron content, and laboratory studies revealed a low serum iron concentration and no detectable serum ceruloplasmin.
Heterozygous Variant
In 3 individuals from 2 unrelated Japanese families with cerebellar ataxia with hypoceruloplasminemia, Miyajima et al. (2001) identified a heterozygous W858X mutation in the CP gene. The patients had onset of cerebellar dysfunction in the fourth decade. Features included relatively nondisabling gait ataxia and dysarthria, as well as hyperreflexia. Brain and abdominal MRI showed cerebellar atrophy and no low-signal intensities in the basal ganglia, thalamus, and liver. The deficiency in serum ceruloplasmin was partial; protein concentrations and ferroxidase activities ranged from 36 to 41% of control values. Serum iron concentration and transferrin saturation were normal. At autopsy, pathologic and biochemical examinations showed marked loss of Purkinje cells, a large iron deposition in the cerebellum, and small depositions in the basal ganglia, thalamus, and liver. Cerebellar ataxia reflected the site of iron deposition. The authors concluded that heterozygosity for mutation of the CP gene can result in cerebellar ataxia.
In 2 brothers with aceruloplasminemia (ACEP; 604290) reported by Logan et al. (1994), Harris et al. (1996) found homozygosity for a 1-bp deletion (c.2389delG) in exon 13 of the CP gene. The nucleotide deletion resulted in a frameshift with change of 11 amino acids and a premature stop codon at codon 789. The nucleotide sequence surrounding this deletion site (TGGAGA) corresponded to a consensus sequence 'hotspot' for nucleotide deletions (Krawczak and Cooper, 1991). The proband had been admitted to hospital at the age of 49 years with a 6-week history of thirst and polyuria and a 2-week history of progressive confusion. Neurologic examination was normal. He was started on a diabetic diet and oral sulfonylurea. At the age of 52, he suddenly left his work one day and was found at home the next day sitting in a chair with the appearance of not having been to bed. When asked why he was not at work he replied, 'What work?' Dementia progressed thereafter, confusion occurring episodically. The younger brother, who worked as a railway laborer, developed diabetes and mental slowing at the age of 47 years. The symptoms seemed to have developed over a period of days and were progressive thereafter. The abnormal ceruloplasmin in this case was referred to as ceruloplasmin Belfast.
In a 56-year-old Japanese man, born of consanguineous parents, with hereditary ceruloplasmin deficiency (ACEP; 604290), Okamoto et al. (1996) identified a homozygous 1-bp insertion (c.184insA) in the CP gene, resulting in a frameshift and premature termination. The patient had systemic hemosiderosis, diabetes mellitus, pigment degeneration of the retina, and neurologic abnormalities.
In 3 affected men from 2 unrelated Indian families (families 3 and 4) with aceruloplasminemia (ACEP; 604290), Vila Cuenca et al. (2020) identified a homozygous G-T transition in intron 10 of the CP gene (c.1864+5G-A), predicted to result in a splicing abnormality. Functional studies of the variant and studies of patient cells were not performed.
Church, W. R., Jernigan, R. L., Toole, J., Hewick, R. M., Knopf, J., Knutson, G. J., Nesheim, M. E., Mann, K. G., Fass, D. N. Coagulation factors V and VIII and ceruloplasmin constitute a family of structurally related proteins. Proc. Nat. Acad. Sci. 81: 6934-6937, 1984. [PubMed: 6438625] [Full Text: https://doi.org/10.1073/pnas.81.22.6934]
Culotta, V. C., Gitlin, J. D. Disorders of copper transport. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (7th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 3105-3126.
Daimon, M., Yamatani, K., Igarashi, M., Fukase, N., Kawanami, T., Kato, T., Tominaga, M., Sasaki, H. Fine structure of the human ceruloplasmin gene. Biochem. Biophys. Res. Commun. 208: 1028-1035, 1995. [PubMed: 7702601] [Full Text: https://doi.org/10.1006/bbrc.1995.1437]
Decker, R. S., Mohrenweiser, H. W. Identification of a new variant of human ceruloplasmin. (Abstract) Am. J. Hum. Genet. 30: 26A, 1978.
Di Meo, I., Tiranti, V. Classification and molecular pathogenesis of NBIA syndromes. Europ. J. Paediat. Neurol. 22: 272-284, 2018. [PubMed: 29409688] [Full Text: https://doi.org/10.1016/j.ejpn.2018.01.008]
Dwulet, F. E., Putnam, F. W. Internal duplication and evolution of human ceruloplasmin. Proc. Nat. Acad. Sci. 78: 2805-2809, 1981. [PubMed: 6942404] [Full Text: https://doi.org/10.1073/pnas.78.5.2805]
Hahn, P., Qian, Y., Dentchev, T., Chen, L., Beard, J., Harris, Z. L., Dunaief, J. L. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc. Nat. Acad. Sci. 101: 13850-13855, 2004. [PubMed: 15365174] [Full Text: https://doi.org/10.1073/pnas.0405146101]
Harris, Z. L., Durley, A. P., Man, T. K., Gitlin, J. D. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Nat. Acad. Sci. 96: 10812-10817, 1999. [PubMed: 10485908] [Full Text: https://doi.org/10.1073/pnas.96.19.10812]
Harris, Z. L., Migas, M. C., Hughes, A. E., Logan, J. I., Gitlin, J. D. Familial dementia due to a frameshift mutation in the caeruloplasmin gene. Quart. J. Med. 89: 355-359, 1996.
Harris, Z. L., Takahashi, Y., Miyajima, H., Serizawa, M., MacGillivray, R. T. A., Gitlin, J. D. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc. Nat. Acad. Sci. 92: 2539-2543, 1995. [PubMed: 7708681] [Full Text: https://doi.org/10.1073/pnas.92.7.2539]
Kellermann, G., Walter, H. On the population genetics of the ceruloplasmin polymorphism. Humangenetik 15: 84-86, 1972. [PubMed: 5046912] [Full Text: https://doi.org/10.1007/BF00273436]
Klomp, L. W. J., Gitlin, J. D. Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum. Molec. Genet. 5: 1989-1996, 1996. [PubMed: 8968753] [Full Text: https://doi.org/10.1093/hmg/5.12.1989]
Koschinsky, M. L., Chow, B. K.-C., Schwartz, J., Hamerton, J. L., MacGillivray, R. T. A. Isolation and characterization of a processed gene for human ceruloplasmin. Biochemistry 26: 7760-7767, 1987. [PubMed: 3427102] [Full Text: https://doi.org/10.1021/bi00398a034]
Koschinsky, M. L., Funk, W. D., van Oost, B. A., MacGillivray, R. T. A. Complete cDNA sequence of human preceruloplasmin. Proc. Nat. Acad. Sci. 83: 5086-5090, 1986. [PubMed: 2873574] [Full Text: https://doi.org/10.1073/pnas.83.14.5086]
Krawczak, M., Cooper, D. N. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum. Genet. 86: 425-441, 1991. [PubMed: 2016084] [Full Text: https://doi.org/10.1007/BF00194629]
Larsen, B. On linkage relations of ceruloplasmin polymorphism (Cp) in cattle. Anim. Blood Groups Biochem. Genet. 8: 111-113, 1977.
Lee, G. R., Nacht, S., Lukens, J. N., Cartwright, G. E. Iron metabolism in copper-deficient swine. J. Clin. Invest. 47: 2058-2069, 1968. [PubMed: 5675426] [Full Text: https://doi.org/10.1172/JCI105891]
Logan, J. I., Harveyson, K. B., Wisdom, G. B., Hughes, A. E., Archbold, G. P. R. Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus. Quart. J. Med. 87: 663-670, 1994. [PubMed: 7820540]
McCombs, M. L., Bowman, B. H., Alperin, J. B. A new ceruloplasmin variant, CP Galveston. Clin. Genet. 1: 30-34, 1970.
McCombs, M. L., Bowman, B. H. Demonstration of inherited ceruloplasmin variants in human serum by acrylamide electrophoresis. Tex. Rep. Biol. Med. 27: 769-772, 1969. [PubMed: 4190683]
Miyajima, H., Kono, S., Takahashi, Y., Sugimoto, M., Sakamoto, M., Sakai, N. Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation. Neurology 57: 2205-2210, 2001. [PubMed: 11756598] [Full Text: https://doi.org/10.1212/wnl.57.12.2205]
Miyajima, H., Nishimura, Y., Mizoguchi, K., Sakamoto, M., Shimizu, T., Honda, N. Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37: 761-767, 1987. [PubMed: 3574673] [Full Text: https://doi.org/10.1212/wnl.37.5.761]
Mohrenweiser, H. W., Decker, R. S. Identification of several electrophoretic variants of human ceruloplasmin including CpMichigan, a new polymorphism. Hum. Hered. 32: 369-373, 1982. [PubMed: 7152528] [Full Text: https://doi.org/10.1159/000153326]
Morita, H., Ikeda, S., Yamamoto, K., Morita, S., Yoshida, K., Nomoto, S., Kato, M., Yanagisawa, N. Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann. Neurol. 37: 646-656, 1995. [PubMed: 7755360] [Full Text: https://doi.org/10.1002/ana.410370515]
Morita, H., Inoue, A., Yanagisawa, N. A case with ceruloplasmin deficiency which showed dementia, ataxia and iron deposition in the brain. Rinsho Shinkeigaku 32: 483-487, 1992. [PubMed: 1458725]
Mukhopadhyay, C. K., Attieh, Z. K., Fox, P. L. Role of ceruloplasmin in cellular iron uptake. Science 279: 714-717, 1998. [PubMed: 9445478] [Full Text: https://doi.org/10.1126/science.279.5351.714]
Naylor, S. L., Yang, F., Cutshaw, S., Barnett, D. R., Bowman, B. H. Mapping ceruloplasmin cDNA to human chromosome 3. (Abstract) Cytogenet. Cell Genet. 40: 711, 1985.
Okamoto, N., Wada, S., Oga, T., Kawabata, Y., Baba, Y., Habu, D., Takeda, Z., Wada, Y. Hereditary ceruloplasmin deficiency with hemosiderosis. Hum. Genet. 97: 755-758, 1996. [PubMed: 8641692] [Full Text: https://doi.org/10.1007/BF02346185]
Osaki, S., Johnson, D. A., Frieden, E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J. Biol. Chem. 241: 2746-2751, 1966. [PubMed: 5912351]
Poulik, M. D. Heterogeneity and structure of ceruloplasmin. Ann. N.Y. Acad. Sci. 151: 476-501, 1968. [PubMed: 4975696] [Full Text: https://doi.org/10.1111/j.1749-6632.1968.tb11909.x]
Riddell, D. C., Wang, H., Royle, N. J., Nigli, M., Guinto, E., Kochinsky, M. L., Irwin, D. M., Cool, D., MacGillivray, R. T. A., Hamerton, J. L. Regional assignment for the human genes encoding FII, FV, FXIII, ceruloplasmin and pseudoceruloplasmin. (Abstract) Cytogenet. Cell Genet. 46: 682, 1987.
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Royle, N. J., Irwin, D. M., Koschinsky, M. L., MacGillivray, R. T. A., Hamerton, J. L. Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively. Somat. Cell Molec. Genet. 13: 285-292, 1987. [PubMed: 3474786] [Full Text: https://doi.org/10.1007/BF01535211]
Schwartzman, A. L., Gaitskhoki, V. S., L'vov, V. M., Nosikov, V. V., Braga, E. M., Frolova, L. Y., Skobeleva, N. A., Kisselev, L. L., Neifakh, S. A. Complex molecular structure of the gene for rat ceruloplasmin. Gene 11: 1-10, 1980. [PubMed: 6254847] [Full Text: https://doi.org/10.1016/0378-1119(80)90081-5]
Shokeir, M. H. K., Shreffler, D. C., Gall, J. C., Jr. Further electrophoretic variation in human ceruloplasmin. (Abstract) American Society of Human Genetics Meeting, Toronto, December 1967.
Shokeir, M. H. K., Shreffler, D. C. Two new ceruloplasmin variants in Negroes--data on three populations. Biochem. Genet. 4: 517-528, 1970. [PubMed: 5456439] [Full Text: https://doi.org/10.1007/BF00486602]
Shreffler, D. C., Brewer, G. J., Gall, J. C., Honeyman, M. S. Electrophoretic variation in human serum ceruloplasmin: a new genetic polymorphism. Biochem. Genet. 1: 101-116, 1967. [PubMed: 4180112] [Full Text: https://doi.org/10.1007/BF00486512]
Stasi, K., Nagel, D., Yang, X., Ren, L., Mittag, T., Danias, J. Ceruloplasmin upregulation in retina of murine and human glaucomatous eyes. Invest. Ophthal. Vis. Sci. 48: 727-732, 2007. [PubMed: 17251471] [Full Text: https://doi.org/10.1167/iovs.06-0497]
Stolc, V. Genetic polymorphism of ceruloplasmin in the rat. J. Hered. 75: 414-415, 1984. [PubMed: 6481132] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a109969]
Takahashi, N., Bauman, R. A., Ortel, T. L., Dwulet, F. E., Wang, C.-C., Putnam, F. W. Internal triplication in the structure of human ceruloplasmin. Proc. Nat. Acad. Sci. 80: 115-119, 1983. [PubMed: 6571985] [Full Text: https://doi.org/10.1073/pnas.80.1.115]
Takahashi, N., Ortel, T. L., Putnam, F. W. Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule. Proc. Nat. Acad. Sci. 81: 390-394, 1984. [PubMed: 6582496] [Full Text: https://doi.org/10.1073/pnas.81.2.390]
Takahashi, Y., Miyajima, H., Shirabe, S., Nagataki, S., Suenaga, A., Gitlin, J. D. Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum. Molec. Genet. 5: 81-84, 1996. [PubMed: 8789443] [Full Text: https://doi.org/10.1093/hmg/5.1.81]
Vila Cuenca, M., Marchi, G., Barque, A., Esteban-Jurado, C., Marchetto, A., Giorgetti, A., Chelban, V., Houlden, H., Wood, N. W., Piubelli, C., Dorigatti Borges, M., Martins de Albuquerque, D., and 17 others. Genetic and clinical heterogeneity in thirteen new cases with aceruloplasminemia: atypical anemia as a clue for an early diagnosis. Int. J. Molec. Sci. 21: 2374, 2020. [PubMed: 32235485] [Full Text: https://doi.org/10.3390/ijms21072374]
Wang, H., Koschinsky, M., Hamerton, J. L. Localization of the processed gene for human ceruloplasmin to chromosome region 8q21.13-q23.1 by in situ hybridization. Cytogenet. Cell Genet. 47: 230-231, 1988. [PubMed: 3416657] [Full Text: https://doi.org/10.1159/000132556]
Weitkamp, L. R. Evidence for linkage between the loci for transferrin and ceruloplasmin in man. Ann. Hum. Genet. 47: 293-297, 1983. [PubMed: 6651218] [Full Text: https://doi.org/10.1111/j.1469-1809.1983.tb00999.x]
Yang, F., Friedrichs, W. E., Cupples, R. L., Bonifacio, M. J., Sanford, J. A., Horton, W. A., Bowman, B. H. Human ceruloplasmin: tissue-specific expression of transcripts produced by alternative splicing. J. Biol. Chem. 265: 10780-10785, 1990. [PubMed: 2355023]
Yoshida, K., Furihata, K., Takeda, S., Nakamura, A., Yamamoto, K., Morita, H., Hiyamuta, S., Ikeda, S., Shimizu, N., Yanagisawa, N. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nature Genet. 9: 267-272, 1995. [PubMed: 7539672] [Full Text: https://doi.org/10.1038/ng0395-267]