Sideroblastic anemia: molecular analysis of ALAS2 gene in a series of 29 probands and functional studies of ten missense mutations

Autor: Ducamp, Sarah, Kannengiesser, Caroline, Touati, Mohamed, Garçon, Loïc, Guerci-Bresler, Agnès, Guichard, Jean-François, Vermylen, Christiane, Dochir, Joaquim, Poirel, Hélène Antoine, Fouyssac, Fanny, Mansuy, Ludovic, Leroux, Geneviève, Tertian, Gérard, Girot, Robert, Heimpel, Hermann, Matthes, Thomas, Talbi, Neila, Deybach, Jean-Charles, Beaumont, Carole, Puy, Hervé, Grandchamp, Bernard
Přispěvatelé: Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Français des Porphyries, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), genetics, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service d'Hématologie biologique [CHU Limoges], CHU Limoges, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Médecine Interne-Pathologie Vasculaire - Immunologie Clinique, Hôpital Sainte Blandine, Génétique Hématologique, Clinique Universitaire Saint-Luc, de Duve Institute, UCL, Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Service d'hématologie clinique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Medizinische Universitätsklinik III, Hôpitaux Universitaires de Genève (HUG)
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: Human Mutation
Human Mutation, Wiley, 2011, 32 (6), pp.590. ⟨10.1002/humu.21455⟩
ISSN: 1059-7794
1098-1004
DOI: 10.1002/humu.21455⟩
Popis: International audience; 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 ten of them, without any published functional characterization, were expressed in E. 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.
Databáze: OpenAIRE
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