title: Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.
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.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Hsiang-Chih
authors.initials: HC
authors.lastname: Lu
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Qiumin
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Maxime W C
authors.initials: MW
authors.lastname: Rousseaux
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ji-Yoen
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ying-Wooi
authors.initials: YW
authors.lastname: Wan
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Szu-Ying
authors.initials: SY
authors.lastname: Yeh
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Patel
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yoontae
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-3174-1480
authors.initials: M
authors.lastname: Chahrour
authors.affiliation: Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas, USA.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas, USA.
authors.forename: Maria E
authors.identifier: http://orcid.org/0000-0002-5055-7208
authors.initials: ME
authors.lastname: Zurita-Jimenez
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Ahimaz
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.affiliation: Centre for Human Genetics, University of Franche-Comté, Besançon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.affiliation: University Hospital Federation, Translational Medicine for Congenital Anomalies (TRANSLAD), Dijon University Hospital, Dijon, France.|Genetic Center and Reference Center for Congenital Anomalies of the East of France, Dijon University Hospital, Dijon, France.|Research Unit 4271, Genetics for Congenital Anomalies, Burgundy University, Dijon, France.
authors.forename: Daphne
authors.initials: D
authors.lastname: Lehalle
authors.affiliation: University Hospital Federation, Translational Medicine for Congenital Anomalies (TRANSLAD), Dijon University Hospital, Dijon, France.|Genetic Center and Reference Center for Congenital Anomalies of the East of France, Dijon University Hospital, Dijon, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Jean-Marcais
authors.affiliation: University Hospital Federation, Translational Medicine for Congenital Anomalies (TRANSLAD), Dijon University Hospital, Dijon, France.|Genetic Center and Reference Center for Congenital Anomalies of the East of France, Dijon University Hospital, Dijon, France.|Research Unit 4271, Genetics for Congenital Anomalies, Burgundy University, Dijon, France.|Chromosomal and Molecular Genetics Laboratory, Biological Center, Dijon University Hospital, Dijon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mosca-Boidron
authors.affiliation: University Hospital Federation, Translational Medicine for Congenital Anomalies (TRANSLAD), Dijon University Hospital, Dijon, France.|Genetic Center and Reference Center for Congenital Anomalies of the East of France, Dijon University Hospital, Dijon, France.|Research Unit 4271, Genetics for Congenital Anomalies, Burgundy University, Dijon, France.
authors.forename: Julien
authors.identifier: http://orcid.org/0000-0001-9271-3961
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Margot A
authors.initials: MA
authors.lastname: Cousin
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Della E
authors.initials: DE
authors.lastname: Bro
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Lanpher
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.|Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Alexander
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Codified Genomics, LLC, Houston, Texas, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.affiliation: Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.|Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Roy V
authors.initials: RV
authors.lastname: Sillitoe
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Ljungberg
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zhandong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Christian P
authors.identifier: http://orcid.org/0000-0002-2148-7490
authors.initials: CP
authors.lastname: Schaaf
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D000067696:Ataxin-1 / Q000235:genetics*; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D000067696:Ataxin-1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins