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Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations
Author(s) -
Ducamp Sarah,
Kannengiesser Caroline,
Touati Mohamed,
Garçon Loïc,
GuerciBresler Agnès,
Guichard Jean François,
Vermylen Christiane,
Dochir Joaquim,
Poirel Hélène A.,
Fouyssac Fanny,
Mansuy Ludovic,
Leroux Geneviève,
Tertian Gérard,
Girot Robert,
Heimpel Hermann,
Matthes Thomas,
Talbi Neila,
Deybach JeanCharles,
Beaumont Carole,
Puy Hervé,
Grandchamp Bernard
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21455
Subject(s) - missense mutation , sideroblastic anemia , biology , genetics , gene , microbiology and biotechnology , mutation , allele
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. Hum Mutat 32:1–8, 2011. © 2011 Wiley‐Liss, Inc.