Abstract
The first feline model of human congenital erythropoietic porphyria (CEP) due to deficient uroporphyrinogen III synthase (URO-synthase) activity was identified by its characteristic clinical phenotype, and confirmed by biochemical and molecular genetic studies. The proband, an adult domestic shorthair cat, had dark-red urine and brownish discolored teeth with red fluorescence under ultraviolet light. Biochemical studies demonstrated markedly increased uroporphyrinogen I in urine and plasma (2,650- and 10,700-fold greater than wild type, respectively), whereas urinary 5-aminolevulinic acid and porphobilinogen were lower than normal. Erythrocytic URO-synthase activity was <1% of mean wild-type activity, confirming the diagnosis and distinguishing it from feline phenocopies having acute intermittent porphyria. Sequencing of the affected cat's UROS gene revealed two missense mutations, c.140C>T (p.S47F) in exon 3 and c.331G>A (p.G111S) in exon 6, both of which were homozygous, presumably owing to parental consanguinity. Neither was present in 100 normal cat alleles. Prokaryotic expression and thermostability studies of the purified monomeric wild-type, p.S47F, p.G111S, and p.S47F/G111S enzymes showed that the p.S47F enzyme had 100% of wild-type specific activity but ~50% decreased thermostability, whereas the p.G111S and p.S47F/G111S enzymes had about 60% and 20% of wild-type specific activity, respectively, and both were markedly thermolabile. Molecular modeling results indicated that the less active/less stable p.G111S enzyme was further functionally impaired by a structural interaction induced by the presence of the S47F substitution. Thus, the synergistic interaction of two rare amino acid substitutions in the URO-synthase polypeptide caused the feline model of human CEP.
Highlights
Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of heme biosynthesis resulting from the markedly deficient, but not absent, activity of uroporphyrinogen III synthase (URO-synthase, EC 4.2.1.75), a characteristic that distinguishes this disorder from feline phenocopies having acute intermittent porphyria (AIP) [1,2]
Biochemical Studies Urinary aminolevulinic acid (ALA) and PBG concentrations were not increased in the proband, whereas the levels of uroporphyrin I (URO I) and coproporphyrin I (COPRO I) were markedly elevated, to ~2,600- and ~245-fold greater than the respective mean wild-type values (Table 1)
Previously, cats who presented with brownish discolored teeth that fluoresced pink under UV light and had increased URO and COPRO concentrations were reported as having a “congenital porphyria” or congenital erythropoietic porphyria (CEP) [24,25,30,31]
Summary
Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of heme biosynthesis resulting from the markedly deficient, but not absent, activity of uroporphyrinogen III synthase (URO-synthase, EC 4.2.1.75), a characteristic that distinguishes this disorder from feline phenocopies having acute intermittent porphyria (AIP) [1,2]. When URO-synthase activity is deficient, the accumulated HMB is nonenzymatically converted to the URO’gen I isomer, which can be enzymatically converted to the metabolic end product, coproporphyrinogen (COPRO’gen) I. The accumulated URO’gen I and COPRO’gen I isomers are oxidized to their corresponding porphyrins, uroporphyrin I (URO I) and coproporphyrin I (COPRO I). Clinical severity depends primarily on the amount of residual URO-synthase activity, and phenotype/genotype correlations have been reported (for example, [5,6]). In CEP, URO I and COPRO I isomers accumulate in erythroid precursors and erythrocytes, which can rupture and release these porphyrins into the circulation, leading to their deposition in skin, tissues and bones, and excretion in the urine and feces. Porphyrin deposition in the teeth and bones causes the clinically diagnostic reddishbrown discolored teeth
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