Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.

远端遗传性运动神经病（HMN）和轴突Charcot-Marie-Tooth神经病（CMT2）是临床和遗传上异质性疾病，主要表现为运动神经元变性和远端无力。尚不清楚约一半受HMN / CMT2影响的个体的遗传原因。在这里，我们报告在四个不相关的家庭中，受散发性或显性HMN / CMT2影响的个体，鉴定出GBF1（高尔基布雷菲德菌素A鸟嘌呤核苷酸交换因子1）中的致病变异。对七个受影响个体的基因组测序分析发现了四个不同的杂合性GBF1变体，其中两个从头发生。其他已知的HMN / CMT2相关基因被排除在外。受影响的个体显示出HMN / CMT2具有缓慢进行性的远端肌肉无力和肌肉骨骼畸形。电生理研究证实，轴突损伤具有慢性神经源性改变。三人有额外的远端感觉丧失。GBF1编码鸟嘌呤-核苷酸交换因子，该因子促进小GTPases的ARF（ADP-核糖基化因子）家族成员的激活。GBF1主要参与涂层蛋白复合物（COPI）囊泡的形成，高尔基体的维持和功能以及线粒体的迁移和定位。我们证明GBF1存在于小鼠脊髓和肌肉组织中，在神经病理相关部位（例如运动神经元和生长锥）中含量特别丰富。与GBF1在高尔基体功能和维持中所描述的作用一致，我们观察到在这项研究中源自所有受影响个体的原代成纤维细胞中高尔基体碎裂的明显增加。GBF1与HMN / CMT2相关联。