ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria

Blood. 2011 Aug 11;118(6):1443-51. doi: 10.1182/blood-2011-03-342873. Epub 2011 Jun 7.


Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Aminolevulinate Synthetase / genetics*
  • 5-Aminolevulinate Synthetase / metabolism
  • Amino Acid Sequence
  • Anemia, Sideroblastic / genetics
  • Anemia, Sideroblastic / metabolism
  • Anemia, Sideroblastic / pathology
  • Base Sequence
  • Child, Preschool
  • Electrophoresis, Polyacrylamide Gel
  • Family Health
  • Female
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / metabolism
  • Genotype
  • Humans
  • Infant
  • Kinetics
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Porphyria, Erythropoietic / genetics*
  • Porphyria, Erythropoietic / metabolism
  • Porphyria, Erythropoietic / pathology
  • Protoporphyria, Erythropoietic / genetics
  • Protoporphyria, Erythropoietic / metabolism
  • Sequence Homology, Amino Acid
  • Severity of Illness Index
  • Spectrophotometry
  • Uroporphyrinogen III Synthetase / genetics*
  • Uroporphyrinogen III Synthetase / metabolism
  • Uroporphyrinogens / metabolism


  • Uroporphyrinogens
  • hydroxymethylbilane
  • 5-Aminolevulinate Synthetase
  • ALAS2 protein, human
  • Uroporphyrinogen III Synthetase

Supplementary concepts

  • X-linked sideroblastic anemia