CP – Aceruloplasminemia

Ceruloplasmin (CP) is a multicopper ferroxidase essential for iron export and homeostasis. Biallelic pathogenic variants in CP lead to aceruloplasminemia, an autosomal recessive disorder characterized by systemic and brain iron accumulation resulting in diabetes mellitus, retinal degeneration, neurodegeneration, and anemia. The diagnosis is often delayed until overt neurological symptoms arise, though biochemical triad features (low ceruloplasmin, low serum iron, hyperferritinemia) are early hallmarks.

Genetic evidence for CP–aceruloplasminemia includes numerous loss-of-function variants. The recurrent nonsense mutation c.2630G>A (p.Trp858Ter) abolishes ferroxidase activity and was identified in multiple unrelated patients (PMID:7708681, PMID:8789443). Over 60 probands carrying biallelic CP variants (including frameshifts, splice-site insertions, and missense mutations) have been reported, spanning at least 25 families, confirming autosomal recessive inheritance and a broad allelic spectrum.

Segregation analysis in several kindreds has demonstrated co-segregation of homozygous or compound heterozygous CP variants with disease phenotypes. For example, siblings homozygous for c.2630G>A (p.Trp858Ter) presented with diabetes and neurodegeneration, confirming variant pathogenicity in a familial context (PMID:8789443).

Functional studies corroborate the pathogenic mechanism as loss of ferroxidase activity and impaired protein trafficking. The missense mutant P177R is retained in the endoplasmic reticulum and fails to be secreted, leading to absent ceruloplasmin activity in vitro (PMID:11689569). Additional site-directed mutagenesis has identified key residues required for copper binding and catalytic function.

Animal models further validate the clinical phenotype: Cp-knockout mice exhibit tissue iron accumulation and neurological deficits, including motor coordination impairment and increased neuronal sensitivity to oxidative stress, recapitulating human aceruloplasminemia (PMID:35147903).

Heterozygous carriers are generally asymptomatic with partial reduction in ceruloplasmin levels; however, some exhibit late-onset cerebellar ataxia, suggesting dosage sensitivity in certain contexts (PMID:11756598). No robust conflicting evidence disputes the CP–aceruloplasminemia link.

Collectively, the CP–aceruloplasminemia association meets criteria for a definitive gene-disease relationship, supported by extensive biallelic genetic findings, segregation in multiple families, and concordant functional and animal data. Early recognition of CP mutations in patients with unexplained iron overload enables timely iron chelation therapy to mitigate neurologic sequelae.

Key Take-Home: Biallelic CP loss-of-function mutations cause aceruloplasminemia; testing CP should be prioritized in unexplained microcytic anemia with low ceruloplasmin and hyperferritinemia to guide early chelation therapy.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1995 • Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. PMID:7708681
• Human molecular genetics • 1996 • Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease. PMID:8789443
• The Journal of Biological Chemistry • 2002 • Biochemical analysis of a missense mutation in aceruloplasminemia. PMID:11689569
• Cell biochemistry and biophysics • 2022 • Ceruloplasmin Deficiency Impaired Brain Iron Metabolism and Behavior in Mice. PMID:35147903

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