title: Candidate gene mutation analysis in idiopathic acquired sideroblastic anemia (refractory anemia with ringed sideroblasts).
abstract: BACKGROUND
  For most cases of idiopathic acquired sideroblastic anemia (IASA), the molecular pathogenesis is unknown, despite the consistent morphological signature of abundant pathological ringed sideroblasts with their characteristic iron-engorged mitochondria. Moderately elevated free erythrocyte protoporphyrin (FEP) levels have been described in IASA, suggesting that the activity of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis (incorporation of ferrous iron into protoporphyrin), might be diminished in erythroid progenitor cells from IASA patients.
  
  
  METHODS
  We confirmed FEP elevation in IASA, then pursued a candidate gene approach that included screening the gene encoding ferrochelatase, FECH, for promoter and coding region mutations and mRNA expression changes in bone marrow from 37 patients with IASA.
  
  
  RESULTS
  The analytical techniques employed detected mutations in a test cohort of previously undiagnosed patients with biochemical evidence for erythropoietic protoporphyria, a condition resulting from germline mutations in FECH, but somatic missense mutations of FECH and its promoter were not observed in IASA patients. FECH was modestly overexpressed in progenitor cells from patients with IASA, compared with MDS patients without sideroblasts and healthy controls. In addition, we analyzed ABCB7 and PUS1, genes implicated in congenital sideroblastic anemia syndromes, but again found no coding mutations in acquired cases.
  
  
  CONCLUSIONS
  We conclude that acquired mutations in the factors currently known to cause inherited sideroblastic anemias are uncommon in IASA.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Steensma.david@mayo.edu
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Hecksel
authors.forename: Julie C
authors.initials: JC
authors.lastname: Porcher
authors.forename: Terra L
authors.initials: TL
authors.lastname: Lasho
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000753:Anemia, Refractory / Q000235:genetics*; D000756:Anemia, Sideroblastic / Q000235:genetics*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004900:Erythroblasts / Q000473:pathology*; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D005294:Ferrochelatase / Q000235:genetics*; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D011524:Protoporphyrins / Q000235:genetics*
chemical_list: C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters; D011524:Protoporphyrins; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase; D005294:Ferrochelatase