Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain.
Ceruloplasmin is a copper-containing ferroxidase that is essential for normal iron homeostasis. Whereas ceruloplasmin in plasma is produced and secreted by hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is expressed on the surface of astrocytes. By using a cDNA cloning approach, we have now determined that the GPI-anchored form of ceruloplasmin is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the C-terminal 5 amino acids of the secreted form with an alternative 30 amino acids that signal GPI anchor addition. RNase protection analysis demonstrates that the GPI-anchored form is the major form in the brain, whereas the secreted form predominates in the liver. Individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin, have severe iron deposition in a number of organs, including the brain where it results in neurodegeneration. Therefore, this novel GPI-anchored form of ceruloplasmin is likely to play an important role in iron metabolism in the central nervous system.
Patel
B N
BN
Center for Research in Neuroscience, The Montreal General Hospital Research Institute and McGill University, Montreal, Quebec H3G 1A4, Canada.
Dunn
R J
RJ
David
S
S
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002570:Ceruloplasmin / Q000737:chemistry* / Q000235:genetics*; D003001:Cloning, Molecular; D015870:Gene Expression; D017261:Glycosylphosphatidylinositols / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D012333:RNA, Messenger / Q000032:analysis; D012260:Ribonucleases; D016415:Sequence Alignment; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D012333:RNA, Messenger; D007501:Iron; D002570:Ceruloplasmin; D012260:Ribonucleases; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase