Aceruloplasminemia is caused by mutations in the CP gene,
located at chromosome 3q21–24.5 The CP gene
encodes the ceruloplasmin protein, a copper oxidase that carries
more than 95% of the plasma copper, and it is also known
as ferroxidase and Fe(II) oxygen oxidoreductase. Ceruloplasmin is essential
in iron hemostasis, catalyzing the oxidation of ferrous to ferric
iron, a change required for the release of iron to plasma transferrin. Ceruloplasmin
has two forms: (1) the plasma α-2-glycoprotein
form, mainly synthesized in hepatocytes and widely expressed, but
unable to enter the brain, and (2) the glycosylphosphatidylinositol–anchored
form, generated by a brain-specific alternative splicing expressed
mainly in astrocytes but also in visceral organs. Mutations in the CP gene
lead to an unstable or nonfunctional ceruloplasmin protein or to
retention of ceruloplasmin at the endoplasmic reticulum. As a consequence
of absence of ceruloplasmin, cells are unable to oxidize and excrete
iron to the extracellular space to be bound by transferrin, and
iron accumulates in hepatocytes, astrocytes, retinal neurons, and
pancreas, among other sites.