Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis
Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis
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DOI：
10.1007/s10048-007-0111-3
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发表时间：
2008-02-01
期刊：
影响因子：
2.2
通讯作者：
Silani, Vincenzo
中科院分区：
文献类型：
--
作者：
Gellera, Cinzia;Colombrita, Claudia;Silani, Vincenzo
血管生成素（Angiogenin， ANG）基因编码一种受缺氧上调的血管生成因子，在腹角运动神经元中表达，是肌萎缩性侧索硬化症（ALS）发病机制的新候选基因。ALS是一种致命的神经退行性疾病，其特征是皮质和脊髓运动神经元的选择性丧失。在北欧和北美的两个ALS人群中发现了ANG基因的错义突变，包括家族性（FALS）和散发性（SALS）患者，但在意大利人群中似乎并不常见。我们对737名意大利ALS患者进行了突变筛查，其中包括605名SALS患者和132名FALS患者。我们在9名患者（6名SALS和3名FALS）中发现了7种不同的突变，其中5种是新的，但在515名健康对照中没有。3个突变位于信号肽区，3个位于编码序列，1个位于3'非翻译区。在我们的ALS人群中，观察到的ANG基因突变频率约占1.2%，与SALS病例（1%）相比，FALS病例（2.3%）的代表性过高。我们还在6名患者和4名对照中发现了先前描述的I46V替代，这表明这种突变可能代表一种良性变异，至少在意大利人群中是这样。我们的研究结果进一步证明了血管生成与ALS发病机制之间的紧密联系，并表明ANG基因突变与ALS发病风险增加有关。
Angiogenin (ANG) gene, coding for an angiogenic factor up-regulated by hypoxia and expressed in ventral horn motor neurons, is a novel candidate for the pathogenesis of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease characterized by the selective loss of cortical and spinal motor neurons. Missense mutations in ANG gene have been identified in two ALS populations from Northern Europe and North America, both in familial (FALS) and sporadic (SALS) patients, but they do not seem to be frequent in the Italian population. We performed a mutational screening in a large cohort of 737 Italian ALS patients, including 605 SALS and 132 FALS cases. We identified seven different mutations, five of which are novel, in nine patients (six SALS and three FALS), but not in 515 healthy controls. Three mutations are located in the signal peptide region, three in the coding sequence, and one in the 3' untranslated region. In our ALS population, the observed mutational frequency of ANG gene accounts for about 1.2%, with an overrepresentation of FALS (2.3%) compared to SALS (1%) cases. We also found the previously described I46V substitution in six patients and four controls, suggesting that this mutation may represent a benign variant, at least in the Italian population. Our results provide further evidence of a tight link between angiogenesis and ALS pathogenesis and suggest that mutations in ANG gene are associated with an increased risk to develop ALS.