The Pathophysiology of CMT2A in Cell and Animal Models

描述（由申请人提供）：腓骨肌萎缩症（CMT）型遗传性神经病是最常见的遗传性神经系统疾病，具有遗传异质性。本申请的主要研究者和1名合作研究者最近确定线粒体融合因子Mitofusin 2（MFN 2）是CMT 2A型（CMT 2A）的病因，CMT 2A是最常见（=20%）的轴突形式的遗传性周围神经病。MFN 2在维持线粒体的融合/分裂平衡中起重要作用。然而，MFN 2突变如何导致人类疾病尚不清楚。在MFN 2敲除小鼠中，-/-小鼠在子宫内死亡，而小鼠没有显示出神经肌肉疾病的迹象。这些结果可能表明这种常染色体显性遗传疾病的功能丧失效应。鉴于PMP 22小鼠在脱髓鞘神经病方面的成功，我们认为为轴突神经病的未来研究提供小鼠模型是重要的，但显然并不容易。本申请旨在将联合收割机人类遗传学与细胞生物学相结合，以开发模拟人类疾病的转基因小鼠模型。基于在CMT患者中发现的突变的这种小鼠模型可能由于以下几个原因而潜在地获得高度重要性：1）与神经病变相关的MFN 2功能障碍的病理生理学是未知的，尽管线粒体功能障碍参与神经肌肉疾病是公认的。2)轴突神经病一般比脱髓鞘形式更常见，但最常见的CMT 2形式CMT 2A的小鼠模型缺失。3)对于轴突型CMT患者没有可用的治疗方法，但最近基于脱髓鞘神经病小鼠模型的研究首次揭示了未来治疗的有希望的结果。

DESCRIPTION (provided by applicant): Hereditary neuropathies of the Charcot-Marie-Tooth (CMT) type comprise the most common inherited neurological disorders and are genetically heterogeneous. The principal investigator and 1 co-investigator on this application have recently identified the mitochondrial fusion factor Mitofusin 2 (MFN2) as a cause for CMT type 2A (CMT2A), the most frequent (=20%) axonal form of hereditary peripheral neuropathies. MFN2 plays a significant role in maintaining the fusion/fission balance for mitochondria. However, how MFN2 mutations lead to a human disease is unknown. In MFN2 knock-out mice the -/- mice died in utero, while the mice showed no signs of neuromuscular disease. These results may indicate loss of function effect for this autosomal dominant disorder. In the light of the success of the PMP22 mouse for demyelinating neuropathies, we think it is important but apparently not easy, to have a mouse model available for future studies of axonal neuropathies. This application aims to combine human genetics with cell biology in order to develop a transgenic mouse model mimicking the human disease. Such a mouse model, based on mutations found in CMT patients, could potentially gain high importance for several reasons: 1) The pathophysiology of MFN2 dysfunction in relation to neuropathies is unknown, although involvement of mitochondrial dysfunction in neuromuscular diseases is well recognized., 2) Axonal neuropathies in general are more frequent then demyelinating forms, but a mouse model for the most common CMT2 form, CMT2A, is missing. 3) There is no treatment available for axonal CMT patients, but recent studies based on mouse models for demyelinating neuropathies revealed for the first time promising results for future treatment.