東京大學(xué)和德島大學(xué)的聯(lián)合研究小組在新一期《美國人類遺傳學(xué)雜志》上報告說,，他們發(fā)現(xiàn)了遺傳性運(yùn)動和感覺神經(jīng)變性病的一個致病基因。這將有助于研發(fā)運(yùn)動神經(jīng)元疾病的治療藥物,。
遺傳性運(yùn)動和感覺神經(jīng)變性病是一種神經(jīng)元疾病,，在成人期發(fā)病后,，表現(xiàn)為運(yùn)動神經(jīng)出現(xiàn)變化，肩和腰等部位的肌肉力量逐漸下降，與肌萎縮側(cè)索硬化癥（俗稱漸凍癥）的癥狀類似,。
研究小組對于家族中有人患此病的日本西部4個家族共32人的血液進(jìn)行了分析,，結(jié)果發(fā)現(xiàn)，在13名已經(jīng)發(fā)病的人體內(nèi),，名為“TFG”基因全部出現(xiàn)變異,，從而證實這種基因可能是該病的致病基因之一。
研究小組發(fā)現(xiàn),，“TFG”基因如果出現(xiàn)變異,，名為“TDP－43”的蛋白質(zhì)就會在細(xì)胞內(nèi)異常蓄積，導(dǎo)致運(yùn)動神經(jīng)細(xì)胞死亡,。此前,，研究人員已知漸凍癥患者的脊髓中都有這種蛋白質(zhì)蓄積。研究小組由此認(rèn)為,，遺傳性運(yùn)動和感覺神經(jīng)變性病與漸凍癥有可能是由于共同的分子機(jī)制而導(dǎo)致運(yùn)動神經(jīng)細(xì)胞死亡的,。（生物谷Bioon.com）
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.
