Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Here, we describe a novel homozygous MFN2 variant, D414V, in a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy. Characterization of patient fibroblasts reveals phenotypes consistent with impaired MFN2 functions and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

中文翻译：

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共济失调，视神经萎缩和感音神经性听力损失患者的MFN2的HR1域中的新变体的表征

MFN2的致病变异导致2A型Charcot-Marie-Tooth病（CMT），并且是CMT轴突亚型的主要原因。CMT2A的特征主要是远端运动无力和肌肉萎缩，严重程度和发病年龄差异很大。值得注意的是，某些MFN2变体也可以导致其他表型，例如视神经萎缩，听力丧失和脂肪营养不良。尽管MFN2和CMT2A之间有明确的联系，但我们对MFN2蛋白功能异常如何导致人类疾病病理的机制理解仍然不完整。缺乏了解部分是由于MFN2在多种细胞中的作用。尽管最初以其在介导线粒体融合中的作用为特征，但MFN2在介导线粒体与其他细胞器之间的相互作用中也起着重要作用，例如内质网和脂质滴。此外，MFN2对线粒体运输，线粒体自噬也很重要，甚至与脂质转移有关。尽管迄今为止已描述了100多种致病性MFN2变体，但只有少数几个在功能上得到了表征，即使在那时，通常也仅针对一种或两种功能进行了表征。在这里，我们描述了一个小脑共济失调，耳聋，失明，以及弥漫性脑和小脑萎缩患者中的新型纯合MFN2变体，D414V。患者成纤维细胞的表征揭示了与受损的MFN2功能一致的表型，并扩大了MFN2变体的表型表现形式，包括小脑性共济失调。甚至与脂质转移有关。尽管迄今为止已描述了100多种致病性MFN2变体，但只有少数几个在功能上得到了表征，即使在那时，通常也仅针对一种或两种功能进行了表征。在这里，我们描述了一个小脑共济失调，耳聋，失明，以及弥漫性脑和小脑萎缩患者中的新型纯合MFN2变体，D414V。患者成纤维细胞的表征揭示了与受损的MFN2功能一致的表型，并扩大了MFN2变体的表型表现形式，包括小脑性共济失调。甚至与脂质转移有关。尽管迄今为止已描述了100多种致病性MFN2变体，但只有少数几个在功能上得到了表征，即使在那时，通常也仅针对一种或两种功能进行了表征。在这里，我们描述了一个小脑共济失调，耳聋，失明，以及弥漫性脑和小脑萎缩患者中的新型纯合MFN2变体，D414V。患者成纤维细胞的表征揭示了与受损的MFN2功能一致的表型，并扩大了MFN2变体的表型表现形式，包括小脑性共济失调。出现小脑共济失调，耳聋，失明以及弥漫性脑小脑萎缩的患者。患者成纤维细胞的表征揭示了与受损的MFN2功能一致的表型，并扩大了MFN2变体的表型表现形式，包括小脑性共济失调。出现小脑共济失调，耳聋，失明以及弥漫性脑小脑萎缩的患者。患者成纤维细胞的表征揭示了与受损的MFN2功能一致的表型，并扩大了MFN2变体的表型表现形式，包括小脑性共济失调。