PT  - JOURNAL ARTICLE
AU  - Jun Sone
AU  - Satomi Mitsuhashi
AU  - Atsushi Fujita
AU  - Takeshi Mizuguchi
AU  - Keiko Mori
AU  - Haruki Koike
AU  - Akihiro Hashiguchi
AU  - Hiroshi Takashima
AU  - Hiroshi Sugiyama
AU  - Yutaka Kohno
AU  - Yoshihisa Takiyama
AU  - Kengo Maeda
AU  - Hiroshi Doi
AU  - Shigeru Koyano
AU  - Hideyuki Takeuchi
AU  - Michi Kawamoto
AU  - Nobuo Kohara
AU  - Tetsuo Ando
AU  - Toshiaki Ieda
AU  - Yasushi Kita
AU  - Norito Kokubun
AU  - Yoshio Tsuboi
AU  - Masahisa Katsuno
AU  - Yasushi Iwasaki
AU  - Mari Yoshida
AU  - Fumiaki Tanaka
AU  - Ikuo K. Suzuki
AU  - Martin C Frith
AU  - Naomichi Matsumoto
AU  - Gen Sobue
TI  - Long-read sequencing identifies GGC repeat expansion in human-specific <em>NOTCH2NLC</em> associated with neuronal intranuclear inclusion disease
AID  - 10.1101/515635
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 515635
4099  - http://biorxiv.org/content/early/2019/01/09/515635.short
4100  - http://biorxiv.org/content/early/2019/01/09/515635.full
AB  - Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult 1–8, but skin biopsy realized its ante-mortem diagnosis 9,10 and many NIID cases have been diagnosed by skin biopsy11,12. Most cases of NIID are sporadic, but several familial cases are known. Using a large NIID family, we conducted linkage mapping, found a 58.1-Mb linked-region at 1p22.1-q21.3 with a maximum logarithm of odds (LOD) score of 4.21, and successfully identified a GGC repeat expansion in the 5’ portion of NOTCH2NLC in all affected members by long-read sequencing, but not in unaffected members. We further found the similar expansions in additional 8 unrelated families with NIID as well as 39 sporadic NIID patients. Repeat-primed PCR consistently detected the GGC repeat expansion in all the familial and sporadic patients diagnosed by skin biopsy, but never in unaffected family members nor 200 controls. This shows that pathogenic changes in a human-specific gene evolutionarily generated by segmental duplication indeed causes a human disease.