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

TitleDisruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.
Publication TypeJournal Article
Year of Publication2017
AuthorsLu, H-C, Tan, Q, Rousseaux, MWC, Wang, W, Kim, J-Y, Richman, R, Wan, Y-W, Yeh, S-Y, Patel, JM, Liu, X, Lin, T, Lee, Y, Fryer, JD, Han, J, Chahrour, M, Finnell, RH, Lei, Y, Zurita-Jimenez, ME, Ahimaz, P, Anyane-Yeboa, K, Van Maldergem, L, Lehalle, D, Jean-Marcais, N, Mosca-Boidron, A-L, Thevenon, J, Cousin, MA, Bro, DE, Lanpher, BC, Klee, EW, Alexander, N, Bainbridge, MN, Orr, HT, Sillitoe, RV, M Ljungberg, C, Liu, Z, Schaaf, CP, Zoghbi, HY
JournalNat Genet
Date Published2017 Apr
KeywordsAnimals, Ataxin-1, Autism Spectrum Disorder, Cerebellum, Female, Humans, Intellectual Disability, Interpersonal Relations, Male, Mice, Nerve Tissue Proteins, Neurodegenerative Diseases, Nuclear Proteins, Phenotype, Repressor Proteins

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.

Alternate JournalNat Genet
PubMed ID28288114
PubMed Central IDPMC5374026
Grant ListR01 HD083809 / HD / NICHD NIH HHS / United States
S10 OD016167 / OD / NIH HHS / United States
F32 NS083091 / NS / NINDS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
R37 NS022920 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P01 HD067244 / HD / NICHD NIH HHS / United States
R37 NS027699 / NS / NINDS NIH HHS / United States
R01 NS027699 / NS / NINDS NIH HHS / United States
R01 NS089664 / NS / NINDS NIH HHS / United States
R01 HD081216 / HD / NICHD NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States

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