Cell Reports
Volume 8, Issue 3, 7 August 2014, Pages 647-655
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CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

https://doi.org/10.1016/j.celrep.2014.06.039Get rights and content
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open access

Highlights

  • 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

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Present address: Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA

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Present address: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA

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Co-senior author