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Congenital erythropoietic porphyria (CEP), also called Gunther disease, is an autosomal recessive cutaneous porphyria characterized by cutaneous photosensitivity, hemolytic anemia, erythrodontia and splenomegaly. The disorder results from loss of function of uroporphyrinogen III synthase (UROS), which catalyzes the fourth step in heme biosynthesis. UROS deficiency leads to accumulation of type I porphyrin isomers, causing phototoxicity and chronic hemolysis (PMID:8621830, PMID:2331520).
Genetic evidence for UROS-CEP is robust. Over 150 unrelated probands have been reported across more than 20 studies, documenting an autosomal recessive inheritance pattern with compound heterozygous and homozygous mutations (e.g., NM_000375.3:c.217T>C (p.Cys73Arg)) (PMID:2331520, PMID:8946173). The mutation spectrum includes missense, frameshift, splice-site and promoter variants, with Cys73Arg representing over 40% of disease alleles. Additional variants such as Val99Ala, Thr228Met, Ser47Pro and Leu4Phe have been identified globally, often correlating with phenotype severity as evidenced by residual enzymatic activities.
Segregation analysis in multiple families demonstrates co-segregation of UROS variants with disease. A Palestinian family exhibited four affected siblings homozygous for the Ser47Pro mutation with one clinically unaffected homozygote demonstrating variable expressivity (PMID:15304101). Prenatal diagnosis confirmed homozygosity for the Cys73Arg allele in an affected fetus (PMID:8821859). Studies of consanguineous pedigrees and sibships reinforced recessive transmission and enabled carrier screening through biochemical and molecular assays.
Functional studies confirm pathogenicity via loss of UROS stability and catalytic activity. E. coli expression of mutant enzymes (e.g., p.Val99Ala, p.Thr228Met) showed absent or markedly reduced activity (PMID:7552139, PMID:9803266). Proteasome inhibition rescued intracellular levels and activity of hotspot mutants Cys73Arg and P248Gln in human cells, and bortezomib treatment in Uros-P248Q knock-in mice reduced porphyrin levels and photosensitivity (PMID:24145442, PMID:16314073). A knock-in mouse model recapitulates CEP features including erythrodontia, hemolytic anemia and photosensitivity with <1% residual UROS activity.
Rare cases of late-onset, mild uroporphyria in heterozygotes or acquired cases associated with myelodysplastic syndrome highlight potential phenotypic modifiers (PMID:27086902, PMID:28865079). These atypical presentations underscore that somatic mosaicism or additional hematological disorders can induce CEP-like porphyrin accumulation in the absence of biallelic germline mutations.
Overall, the genetic and experimental concordance between UROS variants and CEP phenotype satisfies definitive clinical validity criteria, with extensive case reports, segregation, functional assays and animal modeling. The established autosomal recessive mechanism suggests haploinsufficiency and proteasomal degradation of unstable mutants as key pathogenic processes. Standard management includes sun avoidance, blood transfusions and beta-carotene, with hematopoietic stem cell transplantation offering a cure in severe cases. Genetic testing of UROS is essential for diagnosis, carrier detection, prenatal testing, and may guide use of proteasome inhibitors and gene therapy in the future.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongAutosomal recessive segregation in multiple families, >150 probands with diverse UROS coding and promoter mutations Functional EvidenceStrongBiochemical and cellular assays show UROS loss-of-function and rescue by proteasome inhibition; animal knock-in model recapitulates CEP |