title: Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations.
abstract: X-linked Sideroblastic Anemia (XLSA) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. XLSA is due to mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. Thirteen different ALAS2 mutations were identified in 16 out of 29 probands with sideroblastic anemia. One third of the patients were females with a highly skewed X-chromosome inactivation. The identification of seven novel mutations in the ALAS2 gene, six missense mutations, and one deletion in the proximal promoter extends the allelic heterogeneity of XSLA. Most of the missense mutations were predicted to be deleterious, and 10 of them, without any published functional characterization, were expressed in Escherichia coli. ALAS2 activities were assayed in vitro. Five missense mutations resulted in decreased enzymatic activity under standard conditions, and two other mutated proteins had decreased activity when assayed in the absence of exogenous pyridoxal phosphate and increased thermosensitivity. Although most amino acid substitutions result in a clearly decreased enzymatic activity in vitro, a few mutations have a more subtle effect on the protein that is only revealed by in vitro tests under specific conditions.
authors.affiliation: INSERM, Centre de Recherche Biomédicale Bichat-Beaujon, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ducamp
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touati
authors.forename: Loïc
authors.initials: L
authors.lastname: Garçon
authors.forename: Agnès
authors.initials: A
authors.lastname: Guerci-Bresler
authors.forename: Jean François
authors.initials: JF
authors.lastname: Guichard
authors.forename: Christiane
authors.initials: C
authors.lastname: Vermylen
authors.forename: Joaquim
authors.initials: J
authors.lastname: Dochir
authors.forename: Hélène A
authors.initials: HA
authors.lastname: Poirel
authors.forename: Fanny
authors.initials: F
authors.lastname: Fouyssac
authors.forename: Ludovic
authors.initials: L
authors.lastname: Mansuy
authors.forename: Geneviève
authors.initials: G
authors.lastname: Leroux
authors.forename: Gérard
authors.initials: G
authors.lastname: Tertian
authors.forename: Robert
authors.initials: R
authors.lastname: Girot
authors.forename: Hermann
authors.initials: H
authors.lastname: Heimpel
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
authors.forename: Neila
authors.initials: N
authors.lastname: Talbi
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics*; D000328:Adult; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic / Q000235:genetics*; D002648:Child; D005260:Female; D015870:Gene Expression; D040181:Genetic Diseases, X-Linked; D006418:Heme / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007223:Infant; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011487:Protein Conformation; D011524:Protoporphyrins / Q000235:genetics; D049951:X Chromosome Inactivation
chemical_list: D011524:Protoporphyrins; D006418:Heme; D007501:Iron; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human