title: Congenital erythropoietic porphyria. A mild variant with low uroporphyrin I levels due to a missense mutation (A66V) encoding residual uroporphyrinogen III synthase activity.
abstract: METHODS
  Congenital erythropoietic porphyria, an inborn error of heme biosynthesis, results from the deficient activity of the enzyme uroporphyrinogen III synthase. The clinical manifestations in unrelated patients with this autosomal recessive disorder are remarkedly variable, ranging from mild cutaneous involvement to severe transfusion-dependent hemolytic anemia. Biochemical and molecular studies were undertaken to investigate the nature of the unusually mild phenotype in a 15-year-old boy with only cutaneous manifestations.
  
  
  RESULTS
  The proband's levels of total porphyrins, urinary uroporphyrin I, and erythrocyte coproporphyrin I were elevated, but not as dramatically as in other patients with this porphyria. Interestingly, the erythrocyte uroporphyrinogen III synthase activity in the proband was about 21% of the normal mean, indicating the presence of significant residual activity. In cultured lymphoblasts from the proband, his father, and mother, the enzymatic activities were 10%, 70%, and 50% of the normal mean, respectively. Molecular analyses revealed that the proband was heteroallelic for two uroporphyrinogen III synthase missense mutations: the C73R allele inherited from his mother and the A66V allele transmitted by his father. The A66V allele encoded residual enzymatic activity in vitro while the C73R allele did not.
  
  
  CONCLUSIONS
  The A66V allele accounted for the proband's low levels of porphyrin accumulation and mild clinical manifestations. Such genotype-phenotype correlations should provide understanding of the remarkable clinical variability in other patients with this inherited porphyria.
authors.affiliation: Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York, NY 10029.
authors.forename: C A
authors.initials: CA
authors.lastname: Warner
authors.forename: M B
authors.initials: MB
authors.lastname: Poh-Fitzpatrick
authors.forename: E F
authors.initials: EF
authors.lastname: Zaider
authors.forename: S F
authors.initials: SF
authors.lastname: Tsai
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000293:Adolescent; D001120:Arginine / Q000235:genetics; D004920:Erythropoiesis; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011164:Porphyrias / Q000151:congenital* / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D012871:Skin Diseases / Q000151:congenital* / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics*; D014578:Uroporphyrins / Q000096:biosynthesis*; D014633:Valine / Q000235:genetics
chemical_list: D014578:Uroporphyrins; C034103:uroporphyrin I; D001120:Arginine; D014576:Uroporphyrinogen III Synthetase; D014633:Valine