Sideroblastic Anemia: Molecular Analysis of the ALAS2 Gene in a Series of 29 Probands and Functional Studies of 10 Missense Mutations
Sideroblastic Anemia: Molecular Analysis of the ALAS2 Gene in a Series of 29 Probands and Functional Studies of 10 Missense Mutations
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DOI：
10.1002/humu.21455
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发表时间：
2011-06-01
期刊：
影响因子：
3.9
通讯作者：
Grandchamp, Bernard
中科院分区：
文献类型：
--
作者：
Ducamp, Sarah;Kannengiesser, Caroline;Grandchamp, Bernard
X连锁铁粒幼细胞性贫血（XLSA）是铁粒幼细胞性贫血的最常见遗传形式，是一组异质性疾病，其特征在于红系前体细胞线粒体中的铁沉积。XLSA是由于红细胞特异性5-氨基乙酰丙酸合酶（ALAS 2）基因突变所致。在29例铁粒幼细胞性贫血的先证者中，有16例发现了13种不同的ALAS 2突变。三分之一的患者是X染色体失活高度偏斜的女性。ALAS 2基因中的7个新突变、6个错义突变和近端启动子中的1个缺失的鉴定扩展了XSLA的等位基因异质性。大多数的错义突变被预测是有害的，其中10个，没有任何公开的功能特性，在大肠杆菌中表达。体外测定ALAS 2活性。五个错义突变导致在标准条件下的酶活性降低，和其他两个突变的蛋白质有活性降低时，测定在不存在外源性磷酸吡哆醛和增加热敏性。虽然大多数氨基酸取代导致体外酶活性明显降低，但少数突变对蛋白质具有更微妙的影响，仅在特定条件下通过体外试验揭示。Mutat 32：590-597，2011年。(C)2011 Wiley-Liss，Inc.
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: 590-597, 2011. (C) 2011 Wiley-Liss, Inc.