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

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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.

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Figure 1: Deletion of Atxn1Atxn1l or Cic in the developing forebrain results in behavioral abnormalities.
Figure 2: Deletion of Atxn1Atxn1l or Cic in the developing forebrain results in reduced thickness of upper cortical layers.
Figure 3: The histological defects in Emx1-Cre Cic-mutant mice occur postnatally in postmitotic neurons.
Figure 4: Morphological defects in layer 2/3 pyramidal neurons in Emx1-Cre Cic conditional knockout mice.
Figure 5: Deletion of Cic from the hypothalamus and medial amygdala results in abnormal social behavior.
Figure 6: Identification of heterozygous CIC truncating mutations in four families.

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We thank the families for their participation in the study and H. Zheng (Baylor College of Medicine) for providing Neurod6-Cre (NEX-Cre) mice. This project was partly supported by the Genomic and RNA Profiling Core at Baylor College of Medicine and the expert assistance of the core director, L.D. White. We would like to thank the Mayo Clinic Center for Individualized Medicine Investigative and Functional Genomics Program for funding and support. 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 to H.Y.Z. Q.T. was supported by NIH/NINDS F32 NS083091, and M.W.C.R. received support from Canadian Institutes of Health Research Fellowship 201210MFE-290072–173743. H.Y.Z. is an investigator of the Howard Hughes Medical Institute. We thank the RNA In Situ Hybridization Core (supported by Shared Instrumentation grant 1S10OD016167), the Microscopy Core, and the Neuropathology Core at Baylor College of Medicine. All three cores are supported by NIH IDDRC grant U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

Author information

H.-C.L., Q.T., and H.Y.Z. conceived and designed the experiments. H.T.O. and R.V.S. provided critical input to the project. H.L., Q.T., M.W.C.R., W.W., J.-Y.K., R.R., S.-Y.Y., J.M.P., T.L., and M.C.L. performed the experiments. X.L., Y.L., J.D.F., J.H., and M.C. assisted in generating the mouse models. Y.-W.W. and Z.L. performed RNA–seq analysis. M.E.Z.-J. cultured fibroblasts for patient 1. Q.T. performed human fibroblast RNA and protein analysis. H.L., Q.T., R.H.F., Y.L., P.A., K.A.-Y., L.V.M., D.L., N.J.-M., A.-L.M.-B., J.T., M.A.C., D.E.B., B.C.L., E.W.K., N.A., M.N.B., C.P.S., and H.Y.Z. recruited patients, acquired clinical data, or analyzed whole-exome or Sanger sequencing results. H.L., Q.T., and H.Y.Z. drafted the original manuscript, and all authors assisted in editing the manuscript.

Correspondence to Huda Y Zoghbi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–23 and Supplementary Note (PDF 3573 kb)

Supplementary Table 1

Gene expression analysis of Otp-Cre; Cicflox/flox; ROSAfsTRAP and Otp-Cre; ROSAfsTRAP neurons. (XLSX 59 kb)

Supplementary Table 2

Gene set expression analysis of differentially expressed genes between Otp-Cre; Cicflox/flox; ROSAfsTRAP and Otp-Cre; ROSAfsTRAP neurons. (XLSX 13 kb)

Supplementary Table 3

Details of statistical analysis. (XLSX 31 kb)

Supplementary Table 4

Primer sequences used in this study. (XLSX 31 kb)

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Lu, H., Tan, Q., Rousseaux, M. et al. Disruption of the ATXN1–CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet 49, 527–536 (2017) doi:10.1038/ng.3808

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