Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene.

Abstract

To investigate the molecular basis of the phenotypic heterogeneity in congenital erythropoietic porphyria, the mutations in the uroporphyrinogen m synthase gene from unrelated patients were determined. Six missense (L4F, Y19C, V82F, V99A, A104V, and G225S), a nonsense (Q249X), a frameshift (633insA), and two splicing mutations (IVS2+ and IVS9AA+4) were identified. When L4F, Y19C, V82F, V99A, A104V, 633insA, G225S, and Q249X were expressed in Eseherichia cok, only the V82F, V99A, and A104V alleles expressed residual enzymatic activity. Of note, the V82F mutation, which occurs adjacent to the 5' donor site of intron 4, resulted in -54% aberrantly spliced transcripts with exon 4 deleted. Thus, this novel exonic single-base substitution caused two lesions, a missense mutation and an aberrantly spliced transcript. Of the splicing mutations, the IVS2+1 allele produced a single transcript with exon 2 deleted, whereas the IVS9AA+4 allele was alternatively spliced, -26% being normal transcripts and the remainder with exon 9 deleted. The amount of residual activity expressed by each allele provided a basis to correlate genotype with disease severity, thereby permitting genotype/phenotype predictions in this clinically heterogeneous disease. (J. Clin. Invest. 1995. 95:905-912.)

Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria

“…Thus, these four pathogenic erythroid promoter mutations impaired erythroidspecific transcription, caused CEP, and identified functionally important GATA1 and CP2 transcriptional binding elements for erythroid-specific heme biosynthesis. [13][14][15]. However, extensive molecular analysis of the coding and adjacent flanking, intronic, and 5′-and 3′-untranslated sequences did not detect the causative mutations in about 10-15% of mutant alleles from unrelated patients (2,15,16).…”

Suppression of the Barleyuroporphyrinogen III synthaseGene by aDsActivation Tagging Element Generates Developmental Photosensitivity

“…The suppression of Uros expression causes an accumulation of uroporphyrin(ogen) I, presumably due to the nonenzymatic cyclization of excess hydroxyl methylbilane, as has been observed in mammalian cells (Xu et al, 1995;Sassa and Kappas, 2000). In humans, congenital erythropoietic porphyria is a recessive autosomal disorder characterized by a deficiency in Uros.…”

“…In both mammalian species, accumulated hydroxymethyl bilane arising from Uros deficiency spontaneously cyclizes to form uroporphyrinogen I, and large amounts of photoreactive uroporphyrin I are detected in the urine. In both species, however, complete Uros gene knockouts are lethal (Xu et al, 1995;Ged et al, 2006).…”

“…In mammalian cells, excess hydroxymethyl bilane, arising from a deficiency in Uros activity, is known to spontaneously cyclize to form uroporphyrinogen I that is subsequently detected as uroporphyrin I in urine (Xu et al, 1995;Ged et al, 2006). HPLC analysis of leaf extracts from wild-type Golden Promise seedlings and leaf extracts from necrotic 70a3 seedlings identified a large peak in the mutant tissue extract that was minor in control tissue extract ( Figure 5A).…”

An Extremely Rare Case of Congenital Erythropoietic Porphyria Diagnosed In Adulthood with Unusual Life Threatening Complications

“…[4] More than 49 mutations has described and the most common mutation is substitution of amino acid C73R that is associated with severe phenotype. [6] We couldn't perform genetic studies and more detailed biochemical evaluation due to unavailability of these expensive investigations at our setup. The two main differential diagnoses are hepatic erythropoietic porphyria and erythropoietic protoporphyria.…”