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.
Bibliographical noteFunding Information:
The project was supported by grants NIH/NICHD R01 HD081216 and HD083809 to R.H.F.; NIH/NHGRI 1UM1 HG008898-01 to M.N.B.; NIH/NINDS R37 NS22920 to H.T.O.; NIH/NINDS R01 NS089664 to R.V.S.; NIH/NIGMS R01 GM120033, NSF DMS-1263932 and CPRIT RP170387 to Z.L.; and NIH/NINDS R01 NS027699-26 and R37 NS027699-28