title: CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.
abstract: Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive "founder" mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: M Chiara
authors: MC
authors: Manzini
authors: Department of Psychiatry, Research Centre of Montreal Mental Health University Institute, University of Montreal, Montreal, QC H1N 3V2, Canada; University of Montreal Hospital Research Centre, Montreal, QC H2L 2W5, Canada.
authors: Lan
authors: L
authors: Xiong
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors: Ranad
authors: R
authors: Shaheen
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Dimira E
authors: DE
authors: Tambunan
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Stefania
authors: S
authors: Di Costanzo
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Vanessa
authors: V
authors: Mitisalis
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: David J
authors: DJ
authors: Tischfield
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Antonella
authors: A
authors: Cinquino
authors: Department of Child and Adolescent Psychiatry, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors: Mohammed
authors: M
authors: Ghaziuddin
authors: University of Montreal Hospital Research Centre, Montreal, QC H2L 2W5, Canada.
authors: Mehtab
authors: M
authors: Christian
authors: Department of Psychiatry, Research Centre of Montreal Mental Health University Institute, University of Montreal, Montreal, QC H1N 3V2, Canada.
authors: Qin
authors: Q
authors: Jiang
authors: University of Montreal Hospital Research Centre, Montreal, QC H2L 2W5, Canada.
authors: Sandra
authors: S
authors: Laurent
authors: Ma Ayesha Memorial Centre, University of Karachi, Karachi 75350, Pakistan.
authors: Zohair A
authors: ZA
authors: Nanjiani
authors: Autism Institute, Karachi 74000, Pakistan.
authors: Saima
authors: S
authors: Rasheed
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: R Sean
authors: RS
authors: Hill
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Sofia B
authors: SB
authors: Lizarraga
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Danielle
authors: D
authors: Gleason
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors: Diya
authors: D
authors: Sabbagh
authors: Division of Pediatric Neurology, Department of Pediatrics, King Saud University College of Medicine, Riyadh 11461, Saudi Arabia. Electronic address: mustafa_salih05@yahoo.com.
authors: Mustafa A
authors: MA
authors: Salih
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
authors: Fowzan S
authors: FS
authors: Alkuraya
authors: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors: Christopher A
authors: CA
authors: Walsh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; C512283:CC2D1A protein, human; C522738:Cc2d1a protein, mouse