Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria - PubMed (original) (raw)

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Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria

John D Phillips et al. Blood. 2007.

Abstract

Congenital erythropoietic porphyria (CEP), an autosomal recessive disorder, is due to mutations of uroporphyrinogen III synthase (UROS). Deficiency of UROS results in excess uroporphyrin I, which causes photosensitization. We evaluated a 3-year-old boy with CEP. A hypochromic, microcytic anemia was present from birth, and platelet counts averaged 70 x 10(9)/L (70,000/microL). Erythrocyte UROS activity was 21% of controls. Red cell morphology and globin chain labeling studies were compatible with beta-thalassemia. Hb electrophoresis revealed 36.3% A, 2.4% A(2), 59.5% F, and 1.8% of an unidentified peak. No UROS or alpha- and beta-globin mutations were found in the child or the parents. The molecular basis of the phenotype proved to be a mutation of GATA1, an X-linked transcription factor common to globin genes and heme biosynthetic enzymes in erythrocytes. A mutation at codon 216 in the child and on one allele of his mother changed arginine to tryptophan (R216W). This is the first report of a human porphyria due to a mutation in a trans-acting factor and the first association of CEP with thalassemia and thrombocytopenia. The Hb F level of 59.5% suggests a role for GATA-1 in globin switching. A bone marrow allograft corrected both the porphyria and the thalassemia.

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Figures

Figure 1

Figure 1

Generation of uroporphyrinogen III (uro'gen III) by uroporphyrinogen III synthase (UROS). The enzyme catalyzes the cyclization of HMB with concomitant inversion of ring D to yield the III isomer of uro'gen. a indicates acetate; p, propionate.

Figure 2

Figure 2

Wright-Giemsa stain of peripheral-blood film. Anisocytosis, hypochromia, target cells, and polychromasia are evident.

Figure 3

Figure 3

Pedigree of the proband. The R216W GATA1 mutation was found in the proband (IV-2; ←), his mother (III-2), and his maternal grandmother (II-11). Marked anemia and 60% Hb F were found in the proband; a moderate anemia and 4.8% Hb F were found in the grandmother. Both the proband and his grandmother were thrombocytopenic. The grandmother was 1 of 11 siblings, including 5 brothers, and none were known to be anemic. Siblings II-8, II-9, and II-12 collectively had 7 sons (not shown). None were known to be anemic, and none had signs or symptoms of CEP. These findings suggest that the R216W mutation is a new mutation arising in the maternal grandmother. Green box indicates R216W GATA1 mutation; red box, porphyric phenotype; blue box, anemia, thrombocytopenia and high Hb F levels.

Figure 4

Figure 4

Human GATA-1, residues 204-231, of the highly conserved DNA binding N-terminal zinc finger. The numbered residues indicate the locations of mutations that have been described. The mutations and their associated phenotypes are listed below the sequence. The mutation described here is shown in gray.

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