title: ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.
abstract: 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.
authors.affiliation: Biochemistry and Molecular Genetics Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: To-Figueras
authors.forename: Sarah
authors.initials: S
authors.lastname: Ducamp
authors.forename: Jerome
authors.initials: J
authors.lastname: Clayton
authors.forename: Celia
authors.initials: C
authors.lastname: Badenas
authors.forename: Constance
authors.initials: C
authors.lastname: Delaby
authors.forename: Cecile
authors.initials: C
authors.lastname: Ged
authors.forename: Said
authors.initials: S
authors.lastname: Lyoumi
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Hubert
authors.initials: H
authors.lastname: de Verneuil
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero
authors.forename: Herve
authors.initials: H
authors.lastname: Puy
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002675:Child, Preschool; D004591:Electrophoresis, Polyacrylamide Gel; D005192:Family Health; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007223:Infant; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017092:Porphyria, Erythropoietic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046351:Protoporphyria, Erythropoietic / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012720:Severity of Illness Index; D013053:Spectrophotometry; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics* / Q000378:metabolism; D014577:Uroporphyrinogens / Q000378:metabolism
chemical_list: D014577:Uroporphyrinogens; C024393:hydroxymethylbilane; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human; D014576:Uroporphyrinogen III Synthetase