The Pathophysiology of CMT2A in Cell and Animal Models

描述(申请人提供)：遗传性神经疾病的夏科-玛丽-牙齿(CMT)类型包括最常见的遗传性神经疾病，并具有遗传异质性。这一应用的首席研究员和1名合作研究员最近发现线粒体融合因子Mitofusin 2(Mfn2)是CMT 2A型(CMT2A型)的病因，CMT 2A型是遗传性周围神经病中最常见的轴突形式(=20%)。Mfn2在维持线粒体的融合/分裂平衡中起着重要作用。然而，Mfn2突变如何导致人类疾病尚不清楚。在Mfn2基因敲除小鼠中，-/-小鼠在子宫中死亡，而小鼠没有表现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病的功能效应丧失。鉴于PMP22小鼠在脱髓鞘神经病方面的成功，我们认为，拥有一个可用于未来轴突神经病研究的小鼠模型是重要的，但显然并不容易。这项应用旨在将人类遗传学与细胞生物学相结合，以开发出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，这种小鼠模型可能获得高度重要性，原因如下：1)与神经疾病相关的Mfn2功能障碍的病理生理学尚不清楚，尽管线粒体功能障碍与神经肌肉疾病的关系已得到很好的认识。2)轴突神经疾病通常比脱髓鞘形式更常见，但最常见的CMT2形式的小鼠模型CMT2A缺失。3)轴索性CMT患者尚无治疗方法，但最近基于小鼠脱髓鞘神经病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.