AJHG:日本研究人员发现一种神经疾病致病基因TFG

东京大学和德岛大学的联合研究小组在新一期《美国人类遗传学杂志》上报告说，他们发现了遗传性运动和感觉神经变性病的一个致病基因。这将有助于研发运动神经元疾病的治疗药物。

遗传性运动和感觉神经变性病是一种神经元疾病，在成人期发病后，表现为运动神经出现变化，肩和腰等部位的肌肉力量逐渐下降，与肌萎缩侧索硬化症（俗称渐冻症）的症状类似。

研究小组对于家族中有人患此病的日本西部4个家族共32人的血液进行了分析，结果发现，在13名已经发病的人体内，名为“TFG”基因全部出现变异，从而证实这种基因可能是该病的致病基因之一。

研究小组发现，“TFG”基因如果出现变异，名为“TDP－43”的蛋白质就会在细胞内异常蓄积，导致运动神经细胞死亡。此前，研究人员已知渐冻症患者的脊髓中都有这种蛋白质蓄积。研究小组由此认为，遗传性运动和感觉神经变性病与渐冻症有可能是由于共同的分子机制而导致运动神经细胞死亡的

doi:10.1016/j.ajhg.2012.07.014

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The TRK-Fused Gene Is Mutated in Hereditary Motor and Sensory Neuropathy with Proximal Dominant Involvement

Hiroyuki Ishiura, Wataru Sako, Mari Yoshida, Toshitaka Kawarai, Osamu Tanabe, Jun Goto, Yuji Takahashi, Hidetoshi Date, Jun Mitsui, Budrul Ahsan, Yaeko Ichikawa, Atsushi Iwata, Hiide Yoshino, Yuishin Izumi, Koji Fujita, Kouji Maeda, Satoshi Goto, Hidetaka Koizumi, Ryoma Morigaki, Masako Ikemura, Naoko Yamauchi, Shigeo Murayama, Garth A. Nicholson, Hidefumi Ito, Gen Sobue, Masanori Nakagawa, Ryuji Kaji and Shoji Tsuji

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C>T (p.Pro285Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration.