CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

• Published in: Cell reports (Cambridge) 2014-08, Vol.8 (3), p.647-655
• Main Authors: Manzini, M. Chiara, Xiong, Lan, Shaheen, Ranad, Tambunan, Dimira E., Di Costanzo, Stefania, Mitisalis, Vanessa, Tischfield, David J., Cinquino, Antonella, Ghaziuddin, Mohammed, Christian, Mehtab, Jiang, Qin, Laurent, Sandra, Nanjiani, Zohair A., Rasheed, Saima, Hill, R. Sean, Lizarraga, Sofia B., Gleason, Danielle, Sabbagh, Diya, Salih, Mustafa A., Alkuraya, Fowzan S., Walsh, Christopher A.
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Child Development Disorders, Pervasive - genetics; Child Development Disorders, Pervasive - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Homeostasis; Humans; Intellectual Disability - genetics; Intellectual Disability - metabolism; Mice; Mutation; Neurons - cytology; Neurons - metabolism; NF-kappa B - metabolism; Pedigree; Repressor Proteins - genetics; Repressor Proteins - metabolism; Seizures - genetics; Seizures - metabolism; Signal Transduction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.039

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. [Display omitted] •Founder mutations in CC2D1A cause ID, ASD, and seizures•Cc2d1a loss of function reduces dendritic complexity in postmitotic neurons•CC2D1A regulates NF-κB signaling•Modulation of NF-κB activity in knockdown neurons rescues dendritic complexity Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid and may share similar genetic causes. Manzini et al. describe loss-of-function mutations in CC2D1A causing a spectrum of phenotypes, including ASD, ID, and seizures. They then explore the role of Cc2d1a during neuronal differentiation, showing how this protein regulates neuronal morphology and intracellular signaling, particularly affecting the NF-κB pathway. Changes in signaling homeostasis may be responsible for the variable cognitive phenotypes caused by CC2D1A mutations.