The TRK-Fused Gene Is Mutated in Hereditary Motor and Sensory Neuropathy with Proximal Dominant Involvement
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- 作者：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 ; et al.
- 刊名：The American Journal of Human Genetics
- 出版年：2012
- 出版时间：10 August, 2012
- 年：2012
- 卷：91
- 期：2
- 页码：320-329
- 全文大小：1660 K
文摘
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.