Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.

Abstract

Ceruloplasmin is an abundant alpha 2-serum glycoprotein that contains 95% of the copper found in the plasma of vertebrate species. We report here on the identification of a genetic defect in the ceruloplasmin gene in a patient previously noted to have a total absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration. In this patient T2 (transverse relaxation time)-weighted magnetic resonance imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410, resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patient's daughter, which revealed heterozygosity for this same 5-bp insertion. The presence of this mutation in conjunction with the clinical and pathologic findings demonstrates an essential role for ceruloplasmin in human biology and identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism. These findings support previous studies that identified ceruloplasmin as a ferroxidase and are remarkably consistent with recent studies on the essential role of a homologous copper oxidase in iron metabolism in yeast. The clinical and laboratory findings suggest that additional patients with movement disorders and nonclassical Wilson disease should be examined for ceruloplasmin gene mutations.

hCTR1: A human gene for copper uptake identified by complementation in yeast

“…In the blood, copper is bound to ceruloplasmin, albumin, possibly transcuprein, and small molecules, such as histidine. Although the majority of copper is bound to ceruloplasmin and albumin, neither of these two proteins seems to be necessary for normal copper absorption or transport because aceruloplasminia patients (who lack ceruloplasmin) and analbuminemic rats (with albumin deficiency) both have normal copper metabolism (14)(15)(16)34).…”

“…It was suggested that one avenue for uptake is through ceruloplasmin, the most abundant copper-containing protein in the circulation, which might deliver copper to multiple tissues through a ceruloplasmin receptor (10)(11)(12)(13). Later studies on aceruloplasminemic patients indicated that these patients have defects in iron homeostasis, whereas copper metabolism is normal (14)(15)(16). This indicates that ceruloplasmin is at least not necessary for normal copper transport.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Ceruloplasmin is another major copper-binding protein, which functions as a ferroxidase to promote iron export [168,169]. The protein requires copper binding to perform this function, and low copper levels could lead to iron accumulation by impairing ceruloplasminmediated iron export [170].…”

Iron chelation in the treatment of neurodegenerative diseases

“…This notion is witnessed by an increased brain iron content in aceruloplasminemia and neuroferritinopathy which are hereditary disorders caused by dysfunction of proteins involved in the transport and storage of iron, namely in ceruloplasmin [12] and ferritin light chain (FTL) [13]. Iron is essential for many cellular functions, including energy production, DNA synthesis and repair, phospholipid metabolism, myelination and neurotransmitter synthesis [5].…”

“…Aceruloplasminemia is caused by a mutation in the gene coding for ceruloplasmin protein [12]. Systemic iron accumulation is a consequence of the lack of ceruloplasmin ferroxidase activity preventing the cellular iron efflux.…”