You are here

Cell Rep DOI:10.1016/j.celrep.2014.06.039

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

Publication TypeJournal Article
Year of Publication2014
AuthorsM Manzini, C, Xiong, L, Shaheen, R, Tambunan, DE, Di Costanzo, S, Mitisalis, V, Tischfield, DJ, Cinquino, A, Ghaziuddin, M, Christian, M, Jiang, Q, Laurent, S, Nanjiani, ZA, Rasheed, S, R Hill, S, Lizarraga, SB, Gleason, D, Sabbagh, D, Salih, MA, Alkuraya, FS, Walsh, CA
JournalCell Rep
Date Published2014 Aug 07
KeywordsAnimals, Cells, Cultured, Child Development Disorders, Pervasive, DNA-Binding Proteins, Homeostasis, Humans, Intellectual Disability, Mice, Mutation, Neurons, NF-kappa B, Pedigree, Repressor Proteins, Seizures, Signal Transduction

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.


Alternate JournalCell Rep
PubMed ID25066123
PubMed Central IDPMC4334362
Grant ListR01 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