title: Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.
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.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. john.phillips@hsc.utah.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Spangrude
authors.forename: James P
authors.initials: JP
authors.lastname: Kushner
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D005260:Female; D050982:GATA1 Transcription Factor / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017092:Porphyria, Erythropoietic / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D015533:Transcriptional Activation / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human