日本东京大学医院Shoji Tsuji研究组近日取得一项新成果。他们的最新研究发现非编码CGG的重复扩增在神经肌肉疾病中的作用。相关论文于2019年8月发表在《自然—遗传学》上。

神经元核内包涵体病（NIID）和由FMR1中的非编码CGG重复扩增导致的共济失调综合征之间存在许多惊人的相似性，受到这一启发，研究人员直接搜索了重复序列扩增突变，并鉴定到NBPF19（NOTCH2NLC）的CGG重复扩增是引起NIID的原因。进一步由于跟NIID的相似性，研究人员在另外两种疾病中（oculopharyngeal myopathy with leukoencephalopathy和oculopharyngodistal myopathy）的LOC642361/NUTM2B-AS1和 LRP12基因里鉴定到同样的CGG重复扩增。这些发现拓展现有对于序列扩增导致疾病的认知，并进一步强调直接搜索重复序列可以帮助识别疾病背后的突变。

研究人员表示，非编码序列的重复扩增导致了多种神经肌肉疾病，包括肌强直性营养不良、共济失调综合征、脊髓小脑的共济失调、肌萎缩性脊髓侧索硬化症和良性成人家族性肌阵挛癫痫等。

附：英文原文

Title: Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

Author: Hiroyuki Ishiura, Shota Shibata, Jun Yoshimura, Yuta Suzuki, Wei Qu, Koichiro Doi, M. Asem Almansour, Junko Kanda Kikuchi, Makiko Taira, Jun Mitsui, Yuji Takahashi, Yaeko Ichikawa, Tatsuo Mano, Atsushi Iwata, Yasuo Harigaya, Miho Kawabe Matsukawa, Takashi Matsukawa, Masaki Tanaka, Yuichiro Shirota, Ryo Ohtomo, Hisatomo Kowa, Hidetoshi Date, Aki Mitsue, Hiroyuki Hatsuta, Satoru Morimoto, Shigeo Murayama, Yasushi Shiio, Yuko Saito, Akihiko Mitsutake, Mizuho Kawai, Takuya Sasaki, Yusuke Sugiyama, Masashi Hamada, Gaku Ohtomo, Yasuo Terao, Yoshihiko Nakazato, Akitoshi Takeda, Yoshio Sakiyama, Yumi Umeda-Kameyama, Jun Shinmi, Katsuhisa Ogata, Yutaka Kohno, Shen-Yang Lim, Ai Huey Tan, Jun Shimizu, Jun Goto, Ichizo Nishino, Tatsushi Toda, Shinichi Morishita, Shoji Tsuji

Issue&Volume:Volume 51 Issue 8

Abstract: Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

DOI: 10.1038/s41588-019-0458-z

Source:https://www.nature.com/articles/s41588-019-0458-z