Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans

作者：Lu Hsiang Chih; Tan Qiumin; Rousseaux Maxime W C; Wang Wei; Kim Ji Yoen; Richman Ronald; Wan Ying Wooi; Yeh Szu Ying; Patel Jay M; Liu Xiuyun; Lin Tao; Lee Yoontae; Fryer John D; Han Jing; Chahrour Maria; Finnell Richard H; Lei Yunping; Zurita Jimenez Maria E; Ahimaz Priyanka; Anyane Yeboa Kwame; Van Maldergem Lionel; Lehalle Daphne; Jean Marcais Nolwenn; Mosca Boidron Anne Laure; Thevenon Julien; Cousin Margot A; Bro Della E; Lanpher Brendan C

来源：Nature Genetics, 2017, 49(4): 527-+.

DOI：10.1038/ng.3808

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

• 出版日期2017-4