近日，名古屋大学的Gen Sobue研究组与横浜市立大学的Naomichi Matsumoto研究组合作揭示了NOTCH2NLC基因的GGC重复扩增与神经元核内包涵体病的发病相关。该研究论文发表在2019年8月出版的《自然—遗传学》上。

研究人员收集了大约140例NIID病例，其平均发病年龄为59.7岁，其中大多数是散发性和有几例家族性病例。通过分析一个具有几个患者的大型NIID家族的遗传图谱，研究人员在1p22.1-q21.3处确定了一个58.1 Mb大小的相关区域。通过长读长测序，研究人员鉴定了NOTCH2NLC基因5’端区域的GGC重复扩增。此外，研究人员在8个不相关的NIID家族和40个NIID散例中发现了类似的扩增。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。这项工作表明，在人类特异的NOTCH2NLC基因（由分段重复进化而来）中的重复序列扩增能够导致人类疾病。

研究人员表示，神经元核内包涵体病疾病（NIID）是一种进展型神经退行性疾病，特点是神经元和体细胞中存在嗜酸性透明核内包涵体。NIID的临床表现广泛使得生前诊断很困难，但皮肤活检可以进行生前诊断。

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.

DOI: 10.1038/s41588-019-0459-y

Source: https://www.nature.com/articles/s41588-019-0459-y