CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis
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Author
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.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1016/j.celrep.2014.06.039Metadata
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Manzini, M. C., L. Xiong, R. Shaheen, D. E. Tambunan, S. Di Costanzo, V. Mitisalis, D. J. Tischfield, et al. 2015. “CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis.” Cell reports 8 (3): 647-655. doi:10.1016/j.celrep.2014.06.039. http://dx.doi.org/10.1016/j.celrep.2014.06.039.Abstract
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 intra-cellular 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334362/pdf/Terms of Use
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