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

Cell Rep
Authors
Keywords
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.

Year of Publication
2014
Journal
Cell Rep
Volume
8
Issue
3
Pages
647-55
Date Published
2014 Aug 07
ISSN
2211-1247
URL
DOI
10.1016/j.celrep.2014.06.039
PubMed ID
25066123
PubMed Central ID
PMC4334362
Links
Grant list
R01 NS032457 / NS / NINDS NIH HHS / United States
R01 MH083565 / MH / NIMH NIH HHS / United States
R01NS032457 / NS / NINDS NIH HHS / United States
R00 HD067379 / HD / NICHD NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
R01MH083565 / MH / NIMH NIH HHS / United States
R01 NS035129 / NS / NINDS NIH HHS / United States
Howard Hughes Medical Institute / United States
K99 HD067379 / HD / NICHD NIH HHS / United States
R00HD067379 / HD / NICHD NIH HHS / United States