Deng Jianwen, Zhou Binbin, Yu Jiaxi, Han Xiaochen, Fu Jianhui, Li Xiaobin, Xie Xufang, Zhu Min, Zheng Yilei, Guo Xueyu, Li Pidong, Wang Qingqing, Liu Jing, Zhang Wei, Yuan Yun, Yao Sheng, Wang Zhaoxia, Hong Daojun
Department of Neurology, Peking University First Hospital, Beijing, China.
Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China.
J Med Genet. 2022 May;59(5):462-469. doi: 10.1136/jmedgenet-2020-107649. Epub 2021 Mar 25.
GGC repeat expansion in has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID.
Multiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared.
In two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier.
Our study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.
最近发现NOTCH2NLC基因中的GGC重复扩增通过未知的疾病机制与神经元核内包涵体病（NIID）相关。在此，我们探究散发性病例的遗传起源以及NIID中的毒性RNA功能获得机制。
对NIID患者及其可获取的家庭成员进行了多项基因筛查。评估并比较了NIID患者或无症状携带者血液DNA的甲基化状态、肌肉活检中的NOTCH2NLC mRNA水平以及皮肤活检中的RNA病灶。
在两个散发性NIID家族中，我们鉴定出两名临床和病理上无症状的父亲携带大量GGC重复扩增，重复次数超过300次，其后代的重复次数分别为172次和148次。进一步评估发现，两名无症状父亲精子中的GGC重复次数分别仅为63次和98次。无症状携带者NOTCH2NLC基因的CpG岛发生高甲基化，相应地，无症状父亲的NOTCH2NLC mRNA水平降低。GGC重复扩增RNA在NIID患者中形成RNA病灶，并将RNA结合蛋白隔离到p62阳性核内包涵体中，而在对照或无症状携带者中则未出现这种情况。
我们的研究表明，NOTCH2NLC基因中的GGC重复扩增可能在重复次数约为41至300次时具有致病作用。精子中GGC重复扩增的收缩可能是一些散发性或隐性遗传NIID个体中父系偏向起源的一种可能机制。已确定毒性RNA功能获得机制参与了该疾病的发病过程。
