Institute for Ageing and Health, Wolfson Research Centre, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, UK.
Neuropathol Appl Neurobiol. 2011 Feb;37(1):94-113. doi: 10.1111/j.1365-2990.2010.01147.x.
Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.
分子遗传学的进步使人们能够识别出几种涉及小血管的单基因疾病，这些疾病易导致缺血性和出血性中风以及弥漫性白质疾病。我们重点介绍了伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL），同时还回顾了最近描述的几种疾病的分子发病机制，包括伴有皮质下梗死和白质脑病的常染色体隐性遗传性脑动脉病（CARASIL）、伴有脑白质营养不良的视网膜血管病（RVCL）以及胶原类型 IV，α 1（COL4A1）相关疾病。CADASIL 仍然是最常见的遗传性小血管疾病（SVD），由 NOTCH3 基因中的>190 种不同突变引起，该基因编码一种细胞信号受体。突变的 NOTCH3 引发小动脉和小动脉中的血管平滑肌细胞退化，导致复发性腔隙性梗死。丝氨酸蛋白酶 HTRA1 基因突变与 CARASIL 有关。异常的 HTRA1 活性导致转化生长因子-β信号增加，引起多种作用，包括血管纤维化和细胞外基质合成。伴有严重视网膜病变的 RVCL 疾病与 TREX1 基因突变有关，该基因编码一种丰富的 3'-5' DNA 特异性核酸外切酶。TREX1 突变导致酶的功能获得或数量不足。COL4A1 相关疾病具有高度变异性，包括四个主要表型，具有重叠的系统和中枢神经系统特征，包括儿童和成人的 SVD 伴脑内出血。突变的 COL4A1 可能破坏细胞外基质，导致脆弱的血管壁。遗传性 SVD 尽管表型不同，但它们显示了不同缺陷基因的影响如何汇聚在一起，产生特征性的小动脉病和微血管解体，导致血管性认知障碍。
