CPO and Hereditary Coproporphyria

Hereditary coproporphyria is an acute hepatic porphyria that follows an autosomal dominant pattern of inheritance. Multiple independent studies have demonstrated that pathogenic variants in the coproporphyrinogen oxidase (CPO) gene (HGNC:21011) are causally associated with the disease (hereditary coproporphyria, MONDO_0007369). Detailed molecular analyses have identified a range of variant types including missense, nonsense, frameshift, small deletions, and splicing mutations, all of which impair enzyme function. The consistent detection of these variants in numerous unrelated probands and affected families underlines the robustness of this gene-disease association (PMID:7849704, PMID:11309681).

Genetic evidence is bolstered by the observation that affected individuals frequently demonstrate clear segregation of the CPO mutations with the disease phenotype. In one representative study, the detection of a pathogenic allele in multiple family members, accompanied by clinical manifestations, highlights the utility of segregation analysis for diagnostic decision‑making (PMID:9074789). Moreover, the recurrent identification of specific variants, such as the c.982C>T (p.Pro328Ser) mutation, provides further support for the contribution of these genetic alterations to the disease process (PMID:12181641).

At the molecular level, the spectrum of reported CPO variants includes deleterious mutations that lead to reduced enzyme activity. The selected variant c.982C>T (p.Pro328Ser) is representative of the mutations that cause a critical loss of function. This variant, like many others identified in different cohorts, precisely fits the criteria under the HGVS nomenclature, reinforcing its relevance in clinical contexts (PMID:12181641).

Functional studies have consistently shown that expression of mutant CPO proteins, including those derived from the c.982C>T (p.Pro328Ser) allele, results in markedly decreased enzyme activity—often less than 5% of normal. Such experimental data have been obtained from both in vitro expression systems and cellular models, where enzyme assays quantitatively confirm the impact of these mutations on protein function (PMID:9074789, PMID:9888388). These findings form the cornerstone of the functional evidence supporting the gene-disease association.

The integration of genetic and experimental evidence provides a coherent narrative in which multiple pathogenic variant events, demonstrating clear segregation with disease and recapitulated by functional assays, collectively drive the phenotypic manifestations of hereditary coproporphyria. Although additional variants have been reported, the data consistently support a strong association that informs both clinical diagnosis and therapeutic approaches. Furthermore, the autosomal dominant inheritance pattern simplifies the genetic counseling process for affected families.

Key take‑home: The robust evidence linking CPO gene mutations—particularly the recurrent c.982C>T (p.Pro328Ser) variant—with hereditary coproporphyria underscores the clinical utility and diagnostic value of comprehensive molecular testing in patients presenting with acute hepatic porphyria symptoms.

References

• Human molecular genetics • 1994 • Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria PMID:7849704
• Cellular and molecular biology • 1997 • Molecular defects of the coproporphyrinogen oxidase gene in hereditary coproporphyria PMID:9074789
• Human mutation • 1999 • Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update PMID:9888388
• American journal of human genetics • 2001 • Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria PMID:11309681
• Journal of human genetics • 2002 • Two novel mutations and coexistence of the 991C>T and the 1339C>T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria PMID:12181641

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