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迷信家判定神经元核内包容体病病发机制

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  近日,名古屋大年夜学的Gen Sobue研究组与横浜市立大年夜学的Naomichi Matsumoto研究组协作提醒了NOTCH2NLC基因的GGC重复扩增与神经元核内包容体病的病发相干。该研评论辩论文颁布发表在2019年8月出版的《天然—遗传学》上。

  研究人员汇集了大年夜约140例NIID病例,其平均病发年纪为59.7岁,个中大年夜少数是分发性和有几例家族性病例。经过分析一个具有几个患者的大年夜型NIID家族的遗传图谱,研究人员在1p22.1-q21.3处肯定了一个58.1 Mb大年夜小的相干区域。经过长读长测序,研究人员判定了NOTCH2NLC基因5’端区域的GGC重复扩增。另外,研究人员在8个不相干的NIID家族和40个NIID散例中发清晰明了相似的扩增。研究人员只在病人的成纤维细胞中检测到异常反义转录本。这项任务标明,在人类特异的NOTCH2NLC基因(由分段重复退化而来)中的重复序列扩增可以招致人类疾病。

  研究人员表现,神经元核内包容体病疾病(NIID)是一种停顿型神经退行性疾病,特色是神经元和体细胞中存在嗜酸性透明核内包容体。NIID的临床表现遍及使得生前诊断很艰苦,但皮肤活检可以停止生前诊断。

  附:英文原文

  Title: Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

  Author: Jun Sone, Satomi Mitsuhashi, Atsushi Fujita, Takeshi Mizuguchi, Kohei Hamanaka, Keiko Mori, Haruki Koike, Akihiro Hashiguchi, Hiroshi Takashima, Hiroshi Sugiyama, Yutaka Kohno, Yoshihisa Takiyama, Kengo Maeda, Hiroshi Doi, Shigeru Koyano, Hideyuki Takeuchi, Michi Kawamoto, Nobuo Kohara, Tetsuo Ando, Toshiaki Ieda, Yasushi Kita, Norito Kokubun, Yoshio Tsuboi, Kazutaka Katoh, Yoshihiro Kino, Masahisa Katsuno, Yasushi Iwasaki, Mari Yoshida, Fumiaki Tanaka, Ikuo K. Suzuki, Martin C. Frith, Naomichi Matsumoto, Gen Sobue

  Issue&Volume:Volume 51 Issue 8

  Abstract: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult, but skin biopsy enables its ante-mortem diagnosis. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5 region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

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