CPOX – Hereditary Coproporphyria

This summary reviews the association between CPOX (HGNC:2321) and hereditary coproporphyria (MONDO_0007369). The clinical evidence is derived from multiple independent case reports and multi‑patient studies that consistently document biochemical abnormalities, reduced enzyme activity, and the segregation of pathogenic variants with the disease phenotype (PMID:12227458, PMID:11929047).

Genetic investigations across these studies have revealed a diverse spectrum of pathogenic variants, including missense, frameshift, and splice mutations. In particular, the frameshift variant c.856dup (p.Thr286fs) was identified in at least one family, with additional reports highlighting other variants through direct sequencing and MLPA analyses (PMID:9048920). Segregation analyses in these families further support the gene‐disease relationship, as multiple affected relatives have been shown to harbor the mutant allele.

The inheritance pattern for hereditary coproporphyria is autosomal dominant, albeit with reduced penetrance in some instances. The genetic evidence is bolstered by functional data: in vitro assays and enzymatic studies demonstrate that mutant CPOX proteins typically exhibit less than 50% of normal activity. Such experimental findings not only recapitulate the biochemical phenotype observed in patients but also underscore the mechanistic basis for the disease, reinforcing the clinical observations (PMID:24078084).

While some reports describe additional complex genetic scenarios such as digenic inheritance or associations with related porphyrias, the central evidence linking CPOX to hereditary coproporphyria remains robust. Across independent reports, both the genetic and functional assessments are in concordance, thereby establishing a strong gene‑disease association usable in diagnostic decision‑making and genetic counseling.

In summary, the convergence of multiple lines of evidence—including variant detection, familial segregation, and functional impairment of enzymatic activity—substantiates the role of CPOX in hereditary coproporphyria. This integrated evidence base not only informs patient diagnosis and management but also assists in the development of commercially viable diagnostic assays and future scholarly publications.

Key take‑home sentence: The strong, multi‑evidence association between CPOX and hereditary coproporphyria underpins its clinical utility in guiding diagnosis and genetic counseling.

References

• Journal of inherited metabolic disease • 2002 • A molecular, enzymatic and clinical study in a family with hereditary coproporphyria PMID:12227458
• Cellular and molecular biology (Noisy-le-Grand, France) • 2002 • Molecular, immunological, enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary coproporphyria PMID:11929047
• Human genetics • 1997 • A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria PMID:9048920
• Journal of biochemistry • 2013 • The enzyme engineering of mutant homodimer and heterodimer of coproporphyrinogen oxidase contributes to new insight into hereditary coproporphyria and harderoporphyria PMID:24078084

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