Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke.
Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke.
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DOI：
10.1371/journal.pgen.1003807
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Marchuk DA
中科院分区：
文献类型：
--
作者：
Keum S;Lee HK;Chu PL;Kan MJ;Huang MN;Gallione CJ;Gunn MD;Lo DC;Marchuk DA
在缺血性中风期间，脑血管系统的闭塞导致神经细胞死亡（梗塞），但在人群中很难识别自然发生的调节梗塞的遗传因素。在手术诱导的缺血性中风小鼠模型中，我们之前将 Civq1 映射到远端 7 号染色体，作为决定梗塞体积的数量性状基因座。在这项研究中，使用 32 个近交系小鼠品系进行的全基因组关联图谱和对梗塞体积的附加连锁扫描证实，梗塞的大小是由致病基因的祖先等位基因决定的。相互重组同源小鼠中基因分离的 Civq1 基因座精炼了临界区间，并证明梗死面积是由血管（侧支血管解剖）和非血管（神经保护）效应决定的。通过使用区间特异性 SNP 单倍型分析，我们进一步细化了 Civq1 基因座，并将整合素 α L (Itgal) 鉴定为 Civq1 的致病基因之一。 Itgal 是唯一同时表现出菌株特异性氨基酸取代和表达差异的基因。编码 SNP、外显子 30b 中的 5 bp 插入以及该基因剪接变体 (Itgal-003, ENSMUST00000120857) mRNA 和蛋白表达的增加，均与梗塞体积相关。缺乏 Itgal 的小鼠在离体脑切片和体内局灶性脑缺血中都显示出神经元细胞死亡增加。我们的数据表明，Itgal 中的序列变异可调节缺血性脑损伤，并且梗死体积由血管和非血管机制决定。中风是全球第二大死亡原因，也是导致成人残疾的最常见原因。缺血性中风是由脑动脉血流中断引起的，导致大脑灌注区域的神经元损伤（梗死）。尽管在识别中风易感性遗传风险因素方面已经取得了重大进展，但确定决定组织损伤严重程度的遗传因素已被证明更具挑战性。相比之下，实验室近交系小鼠品系的梗塞体积差异很大。使用完善的中风小鼠模型和复杂的遗传分析，我们利用了这些差异并将 Itgal 确定为候选基因之一。我们进一步表明，Itgal 的等位基因变异与近交系小鼠品系中的梗塞体积分离，并且该基因的缺陷会增加中风中的缺血性神经元细胞死亡。
During ischemic stroke, occlusion of the cerebrovasculature causes neuronal cell death (infarction), but naturally occurring genetic factors modulating infarction have been difficult to identify in human populations. In a surgically induced mouse model of ischemic stroke, we have previously mapped Civq1 to distal chromosome 7 as a quantitative trait locus determining infarct volume. In this study, genome-wide association mapping using 32 inbred mouse strains and an additional linkage scan for infarct volume confirmed that the size of the infarct is determined by ancestral alleles of the causative gene(s). The genetically isolated Civq1 locus in reciprocal recombinant congenic mice refined the critical interval and demonstrated that infarct size is determined by both vascular (collateral vessel anatomy) and non-vascular (neuroprotection) effects. Through the use of interval-specific SNP haplotype analysis, we further refined the Civq1 locus and identified integrin alpha L (Itgal) as one of the causative genes for Civq1. Itgal is the only gene that exhibits both strain-specific amino acid substitutions and expression differences. Coding SNPs, a 5-bp insertion in exon 30b, and increased mRNA and protein expression of a splice variant of the gene (Itgal-003, ENSMUST00000120857), all segregate with infarct volume. Mice lacking Itgal show increased neuronal cell death in both ex vivo brain slice and in vivo focal cerebral ischemia. Our data demonstrate that sequence variation in Itgal modulates ischemic brain injury, and that infarct volume is determined by both vascular and non-vascular mechanisms. Stroke is the second leading cause of death and the most common cause of acquired adult disability worldwide. Ischemic stroke is caused by an interruption of blood flow in the cerebral arteries and results in neuronal damage (infarct) to the area of perfusion in the brain. Although significant progress has been made in the identification of genetic risk factors for stroke susceptibility, identification of genetic factors determining the severity of tissue damage has proven more challenging. By contrast, infarct volume varies widely among laboratory inbred mouse strains. Using a well-established mouse model of stroke and complex genetic analysis, we have exploited these differences and identified Itgal as one of the candidate genes. We further show that allelic variation in Itgal segregates with infarct volume among inbred mouse strains and deficiency of the gene increases ischemic neuronal cell death in stroke.
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