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


Date: 22nd July 2019 | Source: Nature Genetics

Authors: Jun Sone, Satomi Mitsuhashi, Atsushi Fujita, Takeshi Mizuguchi, 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, Masahisa Katsuno, Yasushi Iwasaki, Mari Yoshida, Fumiaki Tanaka, Ikuo K Suzuki, Martin C Frith, Naomichi Matsumoto, Gen Sobue.

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 1p22.1–q21.3 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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