title: Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations.
abstract: BACKGROUND
  Sideroblastic anemias are heterogeneous congenital and acquired bone marrow disorders characterized by pathologic iron deposits in mitochondria of erythroid precursors. Among the congenital sideroblastic anemias (CSAs), the most common form is X-linked sideroblastic anemia, due to mutations in 5-aminolevulinate synthase (ALAS2). A novel autosomal recessive CSA, caused by mutations in the erythroid specific mitochondrial transporter SLC25A38, was recently defined. Other known etiologies include mutations in genes encoding the thiamine transporter SLC19A2, the RNA-modifying enzyme pseudouridine synthase 1 (PUS1), a mitochondrial ATP-binding cassette transporter (ABCB7), glutaredoxin 5 (GLRX5), as well as mitochondrial DNA deletions. Despite these known diverse causes, in a substantial portion of CSA cases a presumed genetic defect remains unknown.
  
  
  METHODS
  In the context of the recent discovery of SLC25A38 as a major novel cause, we systematically analyzed a large cohort of previously unreported CSA patients. Sixty CSA probands (28 females, 32 males) were examined for ALAS2, SLC25A38, PUS1, GLRX5, and ABCB7 mutations. SLC19A2 and mitochondrial DNA were only analyzed if characteristic syndromic features were apparent.
  
  
  RESULTS
  Twelve probands had biallelic mutations in SLC25A38. Seven ALAS2 mutations were detected in eight sporadic CSA cases, two being novel. We also identified a novel homozygous null PUS1 mutation and novel mitochondrial DNA deletions in two patients with Pearson syndrome. No mutations were encountered in GLRX5, ABCB7, or SLC19A2.
  
  
  CONCLUSIONS
  The remaining undefined probands (43%) can be grouped according to gender, family, and clinical characteristics, suggesting novel X-linked and autosomal recessive forms of CSA.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Anke K
authors.initials: AK
authors.lastname: Bergmann
authors.forename: Dean R
authors.initials: DR
authors.lastname: Campagna
authors.forename: Erin M
authors.initials: EM
authors.lastname: McLoughlin
authors.forename: Suneet
authors.initials: S
authors.lastname: Agarwal
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Bottomley
authors.forename: Ellis J
authors.initials: EJ
authors.lastname: Neufeld
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000756:Anemia, Sideroblastic / Q000151:congenital / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D054477:Glutaredoxins / Q000235:genetics; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D009154:Mutation; D014481:United States / Q000453:epidemiology
chemical_list: C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters; C516011:GLRX5 protein, human; D054477:Glutaredoxins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; C120043:SLC19A2 protein, human; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase