ABSTRACT

Background: Brain arteriovenous malformations (AVMs) are a relatively infrequent vascular pathology of unknown etiology that, despite their rarity, cause the highest number of hemorrhagic strokes under the age of 30 years. They pose a challenge to all forms of treatment due to their variable morphology, location, size, and, last but not least, evolving nature. MicroRNAs (miRNAs) are non-coding RNA strands that may suppress the expression of target genes by binding completely or partially to their complementary sequences. Single nucleotide polymorphisms (SNPs), as the name implies, are variations in a single nucleotide in the DNA, usually found in the non-coding segments. Although the majority of SNPs are harmless, some located in the proximity of candidate genes may result in altered expression or function of these genes and cause diseases or affect how different pathologies react to treatment. The roles miRNAs and certain SNPs play in the development and growth of AVMs are currently uncertain, yet progress in deciphering the minutiae of this pathology is already visible.

Methods and Results: We performed an electronic Medline (PubMed, PubMed Central) and Google Academic exploration using permutations of the terms: “arteriovenous malformations,” “single nucleotide polymorphisms,” “microRNA,” “non-coding RNA,” and “genetic mutations.” The findings were then divided into two categories, namely the miRNAs and the candidate gene SNPs associated with AVMs respectively. 6 miRNAs and 12 candidate gene SNPs were identified and discussed.

Conclusions: The following literature review focuses on the discoveries made in ascertaining the different implications of miRNAs and candidate gene SNPs in the formation and evolution of brain AVMs, as well as highlighting the possible directions of future research and biological treatment.

Abbreviations: ACVRL1/ALK1: activin receptor-like kinase 1; Akt: protein kinase B; ANGPTL4: angiopoietin-like 4; ANRIL: antisense noncoding RNA in the INK4 locus; AVM: arteriovenous malformation; AVM-BEC: arteriovenous malformation brain endothelial cell; BRCA1: breast cancer type 1 susceptibility protein; CCS: case-control study; CDKN2A/B: cyclin-dependent kinase inhibitor 2A/B; CLTC: clathrin heavy chain; DNA: deoxyribonucleic acid; ERK: extracellular signal-regulated kinase; GPR124: probable G-protein coupled receptor 124; GWAS: genome-wide association study; HHT: hereditary hemorrhagic telangiectasia; HIF1A: hypoxia-inducible factor 1A; IA: intracranial aneurysm; ICH: intracranial hemorrhage; Id-1: inhibitor of DNA-binding protein A; IL-17: interleukin 17; MAP4K3: mitogen-activated protein kinase kinase kinase kinase 3; miRNA: microRNA; MMP: matrix metalloproteinase; NFkB: nuclear factor kappa-light-chain of activated B cells; NOTCH: neurogenic locus notch homolog; p38MAPK: p38 mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; RBBP8: retinoblastoma-binding protein 8; RNA: ribonucleic acid; SNAI1: Snail Family Transcriptional Repressor 1; SNP: single nucleotide polymorphism; SOX-17: SRY-related HMG-box; TGF-β: transformation growth factor β; TGFR: transformation growth factor receptor; TIMP-4, tissue inhibitor of metalloproteinase 4; TSP-1: thrombospondin-1; UTR: untranslated region; VEGF: Vascular Endothelial Growth Factor; VSMC: vascular smooth muscle cell; Wnt1: Wnt family member 1

摘要

背景：脑动静脉畸形 (AVM) 是一种相对罕见的病因不明的血管病理学，尽管罕见，但在 30 岁以下引起出血性中风的人数最多。由于它们的形态、位置、大小以及最后但并非最不重要的不断变化的性质，它们对所有形式的治疗提出了挑战。MicroRNA (miRNA) 是非编码 RNA 链，可通过完全或部分结合目标基因的互补序列来抑制目标基因的表达。顾名思义，单核苷酸多态性 (SNP) 是 DNA 中单个核苷酸的变异，通常在非编码片段中发现。尽管大多数 SNP 是无害的，一些位于候选基因附近的可能会导致这些基因的表达或功能发生改变，并导致疾病或影响不同病理对治疗的反应。miRNA 和某些 SNP 在 AVM 的发育和生长中所起的作用目前还不确定，但破译这种病理细节的进展已经是可见的。

方法和结果：我们使用以下术语的排列进行了电子 Medline（PubMed、PubMed Central）和 Google Academic 探索：“动静脉畸形”、“单核苷酸多态性”、“microRNA”、“非编码 RNA”和“遗传突变。” 然后将这些发现分为两类，即分别与 AVM 相关的 miRNA 和候选基因 SNP。鉴定并讨论了 6 个 miRNA 和 12 个候选基因 SNP。

结论：以下文献综述侧重于在确定 miRNA 和候选基因 SNP 在脑 AVM 形成和进化中的不同影响方面取得的发现，并强调了未来研究和生物治疗的可能方向。

缩写：ACVRL1/ALK1：激活素受体样激酶1；Akt：蛋白激酶 B；ANGPTL4：血管生成素样 4；ANRIL：INK4 基因座中的反义非编码 RNA；AVM：动静脉畸形；AVM-BEC：动静脉畸形脑内皮细胞；BRCA1：乳腺癌1型易感蛋白；CCS：病例对照研究；CDKN2A/B：细胞周期蛋白依赖性激酶抑制剂 2A/B；CLTC：网格蛋白重链；DNA：脱氧核糖核酸；ERK：细胞外信号调节激酶；GPR124：可能的 G 蛋白偶联受体 124；GWAS：全基因组关联研究；HHT：遗传性出血性毛细血管扩张症；HIF1A：缺氧诱导因子1A；IA：颅内动脉瘤；ICH：颅内出血；Id-1：DNA结合蛋白A的抑制剂；IL-17：白细胞介素 17；MAP4K3：丝裂原活化蛋白激酶激酶激酶3；miRNA：微小RNA；MMP：基质金属蛋白酶；NFkB：活化 B 细胞的核因子 kappa-轻链；NOTCH：神经源性基因座缺口同源物；p38MAPK：p38 丝裂原活化蛋白激酶；PI3K：磷酸肌醇 3-激酶；RBBP8：视网膜母细胞瘤结合蛋白 8；RNA：核糖核酸；SNAI1：蜗牛家族转录抑制因子1；SNP：单核苷酸多态性；SOX-17：SRY相关的HMG-box；TGF-β：转化生长因子β；TGFR：转化生长因子受体；TIMP-4，金属蛋白酶4的组织抑制剂；TSP-1：血小板反应蛋白-1；UTR：非翻译区；VEGF：血管内皮生长因子；VSMC：血管平滑肌细胞；Wnt1：Wnt 家庭成员 1 磷酸肌醇 3-激酶；RBBP8：视网膜母细胞瘤结合蛋白 8；RNA：核糖核酸；SNAI1：蜗牛家族转录抑制因子1；SNP：单核苷酸多态性；SOX-17：SRY相关的HMG-box；TGF-β：转化生长因子β；TGFR：转化生长因子受体；TIMP-4，金属蛋白酶4的组织抑制剂；TSP-1：血小板反应蛋白-1；UTR：非翻译区；VEGF：血管内皮生长因子；VSMC：血管平滑肌细胞；Wnt1：Wnt 家庭成员 1 磷酸肌醇 3-激酶；RBBP8：视网膜母细胞瘤结合蛋白 8；RNA：核糖核酸；SNAI1：蜗牛家族转录抑制因子1；SNP：单核苷酸多态性；SOX-17：SRY相关的HMG-box；TGF-β：转化生长因子β；TGFR：转化生长因子受体；TIMP-4，金属蛋白酶4的组织抑制剂；TSP-1：血小板反应蛋白-1；UTR：非翻译区；VEGF：血管内皮生长因子；VSMC：血管平滑肌细胞；Wnt1：Wnt 家庭成员 1 VEGF：血管内皮生长因子；VSMC：血管平滑肌细胞；Wnt1：Wnt 家庭成员 1 VEGF：血管内皮生长因子；VSMC：血管平滑肌细胞；Wnt1：Wnt 家庭成员 1