UROD – Familial Porphyria Cutanea Tarda

Familial porphyria cutanea tarda (fPCT) is an autosomal dominant cutaneous porphyria characterized by adult onset of skin fragility, hyperpigmentation, photosensitivity and hypertrichosis. Heterozygous loss-of-function variants in UROD, encoding uroporphyrinogen decarboxylase, lead to ~50% residual enzyme activity in all tissues, causing accumulation of highly carboxylated porphyrins in the liver and skin. The rare homozygous form (hepatoerythropoietic porphyria) presents in childhood with more severe manifestations.

Multiple large cohorts have confirmed the association of UROD variants with fPCT. A Spanish study of 61 unrelated PCT patients identified 16 fPCT probands with 14 distinct UROD mutations, including 10 novel alleles (PMID:17627795). Italian and international surveys have similarly reported over 120 unrelated fPCT cases with private and recurrent variants (PMID:11295834).

Segregation analysis across numerous pedigrees demonstrates co-segregation of UROD variants with fPCT in affected relatives; in one series, 19 additional family members were heterozygous carriers with reduced enzyme activity (PMID:8644733).

The UROD variant spectrum in fPCT comprises at least 29 pathogenic alleles: approximately 14 missense substitutions (e.g., c.842G>A (p.Gly281Glu)), 7 nonsense/frameshift mutations, and 6 canonical splice-site defects, plus regulatory 3′-UTR changes. The p.Gly281Glu allele is a common founder mutation in Spain, observed on multiple haplotype backgrounds (PMID:23545314).

Functional assays of recombinant UROD mutants uniformly show markedly reduced decarboxylase activity and increased thermolability. Site-directed P62L and Y311C variants expressed in bacterial systems retain <20% wild-type activity and exhibit heat-induced denaturation (PMID:8644733; PMID:8896428). Novel Spanish missense alleles similarly demonstrate decreased stability in prokaryotic expression models (PMID:17627795).

No studies have refuted the UROD–fPCT link, and all reported variants are absent or extremely rare in population databases. The weight of genetic and biochemical data supports a definitive gene–disease relationship.

Key take-home: UROD haploinsufficiency causes autosomal dominant fPCT, enabling targeted genetic testing for diagnosis, carrier screening and familial counselling.

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
• Human Mutation • 1999 • Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis. PMID:10477430
• Human Mutation • 2001 • Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT). PMID:11295834
• 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
• Gene • 2013 • Familial porphyria cutanea tarda in Spain: characterization of eight novel mutations in the UROD gene and haplotype analysis of the common p.G281E mutation. PMID:23545314

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