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Nat Genet. 2017 Apr;49(4):527-536. doi: 10.1038/ng.3808. Epub 2017 Mar 13.

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

Lu HC1,2, Tan Q2,3, Rousseaux MW2,3, Wang W2,3, Kim JY2,3, Richman R2,3,4, Wan YW2,3, Yeh SY1,2, Patel JM5, Liu X2,3,4, Lin T2,6, Lee Y2,3, Fryer JD2,3, Han J2,3, Chahrour M3, Finnell RH7, Lei Y7, Zurita-Jimenez ME7, Ahimaz P8, Anyane-Yeboa K8, Van Maldergem L9, Lehalle D10,11,12, Jean-Marcais N10,11, Mosca-Boidron AL10,11,12,13, Thevenon J10,11,12, Cousin MA14,15, Bro DE14,16, Lanpher BC14,16, Klee EW14,15,16, Alexander N17, Bainbridge MN3,18,19, Orr HT20,21, Sillitoe RV1,2,5,6, Ljungberg MC2,22, Liu Z2,22, Schaaf CP2,3,23, Zoghbi HY1,2,3,4,5,22.

Author information

1
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.
2
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
4
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
5
Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
6
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
7
Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas, USA.
8
Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
9
Centre for Human Genetics, University of Franche-Comté, Besançon, France.
10
University Hospital Federation, Translational Medicine for Congenital Anomalies (TRANSLAD), Dijon University Hospital, Dijon, France.
11
Genetic Center and Reference Center for Congenital Anomalies of the East of France, Dijon University Hospital, Dijon, France.
12
Research Unit 4271, Genetics for Congenital Anomalies, Burgundy University, Dijon, France.
13
Chromosomal and Molecular Genetics Laboratory, Biological Center, Dijon University Hospital, Dijon, France.
14
Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
15
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
16
Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
17
GeneDx, Gaithersburg, Maryland, USA.
18
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
19
Codified Genomics, LLC, Houston, Texas, USA.
20
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.
21
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
22
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
23
Texas Children's Hospital, Houston, Texas, USA.

Abstract

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.

PMID:
28288114
PMCID:
PMC5374026
DOI:
10.1038/ng.3808
[Indexed for MEDLINE]
Free PMC Article

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