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Ceruloplasmin (Cp) biosynthesis. Several different mechanisms by which CP pathogenic missense variants result in the lack of enzymatic activity. As p.Pro177Arg, p.Gly176Arg, and p.Ile9Phe mutated protein is retained in the endoplasmic reticulum, aceruloplasminemia is caused by defects in protein trafficking. Pathogenic variants p.Gly631Arg, p.Ala331Asp, and p.Met966Val cause CP deficiency through other mechanisms: indirect dysfunction of a copper-binding site or other structural abnormalities in the protein that prevent the incorporation of copper (Cu) into CP. Protein variant p.His978Gln has no ferroxidase activity. Protein variants p.Gln146Glu and p.Gly876Ala degrade rapidly when holoceruloplasmin is secreted into the extracellular space. In this figure, the numbering of amino acid residues is based on the mature protein after cleavage of the 19-amino-acid signal peptide.

Note: Pathogenic variants and their nomenclature in Figure 4 were provided by the author (H Miyajima) and not reviewed by GeneReviews staff.