Ceruloplasmin genes

Ceruloplasmin is a protein for which many functions have been proposed - somewhat akin to Pirandello s Six Characters in Search of an Author, ceruloplasmin has long been a protein in search of a function. However, its importance in iron metabolism has been underlined by the observation of systemic iron loading in the tissues of patients with aceruloplasminaemia and other mutations in the ceruloplasmin gene. For further information on copper and iron interactions, see Chapter 12. 

Aceruloplasminaemia is a very rare, autosomal recessive disease with diffuse iron overload. It is caused by a mutation of the ceruloplasmin gene. This leads to excessive iron storage, mainly in the brain, liver and pancreas. The principal symptoms are increased serum ferritin, decreased serum iron and transferrin saturation as well as extrapyramidal disturbances, retinal degeneration, cerebellar ataxia and diabetes mellitus. (486-488) (s. tab. 31.17)... 

Yoshida, K., Furihata, K., Takeda, S., Nakamura, A., Yamamoto, K., Morita, H., TUyamuta, S., Ikeda, S., Shimizu, N., Yanagisawa, N. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nature Genet. 1995 9 267-272... 

Gitlin, J. D. (1968). Transcriptional regulation of ceruloplasmin gene expression during inflammation. J- Bio . Otem. 263,6231-6287. 

Garey CE> Schwarznian AL, Rise ML, Seyfiried TN. Ceruloplasmin gene defect associated with epilepsy in EL mice. Nat Genet 1994 6 426-31. 

Yang F, Naylor SL, Lum JB, Cutshaw S, McCombs JL, Naberhaus KH, et al. Characterization, mapping, and expression of the human ceruloplasmin gene, Proc Natl Acad Sci USA 1986 83 3257-61. 

Ceruloplasmin has long been thought to be a ferroxidase and it has been proposed that ceruloplasmin has a custodial role in vivo, ensuring that Fe " " released from cells is oxidised to the potentially less toxic Fe + prior to its incorporation into apotransferrin. Aceruloplasminaemia is a neurodegenerative disease associated with the absence of functional ceruloplasmin due to the presence of inherited mutations within the ceruloplasmin gene. This condition results in disruption of iron homeostasis, with extensive iron accumulation in a number of tissues... 

Mercer and Grimes (183) have reported the isolation and characterization of a human ceruloplasmin cDNA clone extending from the amino-terminal leader sequence to 114 amino acid residues 5 to the carboxy-terminus of the protein. Interestingly, the reported 5 untranslated region of 14 bp differs completely from that determined by Koschinsky et al. (unpublished data). The signal peptide region in both clones is identical however, the nature of this discrepancy is unclear and awaits characterization of the 5 end of the ceruloplasmin gene for clarification. 

The rat ceruloplasmin cDNA clone described above was further used to identify extrahepatic sites of ceruloplasmin gene expression in the rat. Although the liver was originally postulated to be the sole tissue source of ceruloplasmin (189), the above study resulted in the detection of ceruloplasmin mRNA in the choroid plexus, yolk sac, placenta and testis of the rat. Since these tissues are situated at the interface between adjacent extracellular compartments, it has been suggested that ceruloplasmin may be involved in maintaining copper homeostasis in these compartments (189). 

All processed pseudogenes studied to date are located on different chromosomes from those of their functional counterparts (191). With previously characterized human-hamster hybrid cell lines, the ceruloplasmin pseudogene has been mapped to chromosome 8 (194). This differs from the assignment of the functional ceruloplasmin gene to chromosome 3 (87,182). 

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