UROD – Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT; MONDO:0015104) is the most common cutaneous porphyria, resulting from partial deficiency of uroporphyrinogen decarboxylase (UROD; HGNC:12591) activity in hepatocytes. Familial PCT (type II) is inherited as an autosomal dominant trait with incomplete penetrance, whereas sporadic PCT (type I) arises from acquired hepatic UROD inhibition. UROD heterozygous loss-of-function variants confer a 50% reduction in systemic enzyme activity and predispose to clinically overt PCT when combined with secondary triggers such as iron overload, hepatitis C virus infection or alcohol use.

Genetic evidence for UROD in PCT is compelling. Familial PCT segregates UROD variants across at least 61 unrelated kindreds, with 14 distinct alleles identified (e.g., c.430C>T (p.Arg144Ter)) and confirmed in affected relatives [PMID:17627795]. In a Norwegian cohort of 253 PCT patients, 53% harbored deleterious UROD mutations [PMID:19233912], and additional studies report over 200 probands with pathogenic missense, nonsense, splice-site and frameshift alleles. Segregation of UROD variants in 19 affected relatives underscores autosomal dominant transmission.

Functionally, UROD variants impair enzyme stability and activity. Recombinant missense substitutions (e.g., p.Pro62Leu, p.Tyr311Cys) exhibit <15% residual decarboxylase function and increased thermolability, while truncating alleles abolish catalytic activity entirely [PMID:8644733; PMID:8896428]. Hepatoerythropoietic porphyria, the recessive form, arises from homozygous or compound heterozygous UROD mutations producing profound systemic deficiency and early childhood onset.

Secondary factors modulate PCT penetrance in UROD heterozygotes. Cohort studies demonstrate that co-inheritance of HFE hemochromatosis alleles accelerates disease onset, with C282Y homozygosity linked to earlier skin lesions [PMID:11069625]. Hepatitis C virus, alcohol abuse and estrogen therapy further lower hepatic UROD activity, triggering porphyrin accumulation and photosensitive blistering.

Pathogenicity in PCT is driven by haploinsufficiency of UROD in the liver. Molecular diagnostics combining UROD gene sequencing and erythrocyte activity assays effectively distinguish familial from sporadic cases and identify asymptomatic carriers. Early genetic confirmation guides clinical management by informing surveillance for iron overload and avoiding precipitating exposures.

Key take-home: Germline UROD mutations cause autosomal dominant familial PCT with incomplete penetrance; genetic testing is essential for diagnosis, family counseling and tailored preventive strategies.

References

• American journal of human genetics • 1996 • Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria PMID:8644733
• Blood • 1996 • Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria PMID:8896428
• Scandinavian journal of clinical and laboratory investigation • 2000 • Uroporphyrinogen decarboxylase gene mutations in Danish patients with porphyria cutanea tarda PMID:11202053
• Clinical chemistry • 2009 • Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies PMID:19233912
• The British journal of dermatology • 2007 • Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene PMID:17627795
• The Journal of investigative dermatology • 2000 • Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda PMID:11069625

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