MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK.
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Dis Model Mech. 2014 Jun;7(6):711-22. doi: 10.1242/dmm.015222. Epub 2014 Apr 24.
Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18-mutant mouse model of WARBM. Rab18-mutant mice are viable and fertile. They present with congenital nuclear cataracts and atonic pupils, recapitulating the characteristic ocular features that are associated with WARBM. Additionally, Rab18-mutant cells exhibit an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of cells taken from WARBM individuals, as well as cells taken from individuals with other neurodegenerative conditions. Neurological dysfunction is also apparent in Rab18-mutant mice, including progressive weakness of the hind limbs. We show that the neurological defects are, most likely, not caused by gross perturbations in synaptic vesicle recycling in the central or peripheral nervous system. Rather, loss of Rab18 is associated with widespread disruption of the neuronal cytoskeleton, including abnormal accumulations of neurofilament and microtubule proteins in synaptic terminals, and gross disorganisation of the cytoskeleton in peripheral nerves. Global proteomic profiling of peripheral nerves in Rab18-mutant mice reveals significant alterations in several core molecular pathways that regulate cytoskeletal dynamics in neurons. The apparent similarities between the WARBM phenotype and the phenotype that we describe here indicate that the Rab18-mutant mouse provides an important platform for investigation of the disease pathogenesis and therapeutic interventions.
RAB18 基因突变已被证实可导致异质性常染色体隐性遗传疾病 Warburg 微综合征（WARBM）。WARBM 患者表现出一系列临床症状，包括眼部和神经系统异常。然而，该疾病的潜在细胞和分子发病机制仍不清楚，这主要是因为缺乏任何能够模拟疾病的眼部和神经系统特征的稳健动物模型。我们在此报告一种新型 WARBM 的 Rab18 突变小鼠模型的生成和特征。Rab18 突变小鼠具有活力和繁殖力。它们表现出先天性核性白内障和弛缓性瞳孔，再现了与 WARBM 相关的特征性眼部特征。此外，Rab18 突变细胞在用油酸处理后表现出脂滴大小增加。脂滴异常是来自 WARBM 个体以及来自其他神经退行性疾病个体的细胞的特征性特征。Rab18 突变小鼠也表现出神经功能障碍，包括后肢逐渐无力。我们表明，神经缺陷很可能不是由于中枢或周围神经系统中突触囊泡再循环的严重扰动引起的。相反，Rab18 的缺失与神经元细胞骨架的广泛破坏有关，包括突触末端神经丝和微管蛋白的异常积累，以及周围神经中细胞骨架的严重紊乱。Rab18 突变小鼠周围神经的全蛋白质组学分析揭示了几个核心分子途径的显著改变，这些途径调节神经元中的细胞骨架动力学。WARBM 表型和我们在此描述的表型之间的明显相似性表明，Rab18 突变小鼠为研究疾病发病机制和治疗干预提供了重要平台。
