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Cell Rep. 2014 Aug 7;8(3):647-55. doi: 10.1016/j.celrep.2014.06.039. Epub 2014 Jul 24.

CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.

Author information

1
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.
2
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.
3
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
4
Department of Child and Adolescent Psychiatry, University of Michigan Health System, Ann Arbor, MI 48109, USA.
5
University of Montreal Hospital Research Centre, Montreal, QC H2L 2W5, Canada.
6
Department of Psychiatry, Research Centre of Montreal Mental Health University Institute, University of Montreal, Montreal, QC H1N 3V2, Canada.
7
Ma Ayesha Memorial Centre, University of Karachi, Karachi 75350, Pakistan.
8
Autism Institute, Karachi 74000, Pakistan.
9
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.
10
Division of Pediatric Neurology, Department of Pediatrics, King Saud University College of Medicine, Riyadh 11461, Saudi Arabia. Electronic address: mustafa_salih05@yahoo.com.
11
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
12
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.

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.

PMID:
25066123
PMCID:
PMC4334362
DOI:
10.1016/j.celrep.2014.06.039
[Indexed for MEDLINE]
Free PMC Article
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