Document Type
Journal Article
Publication Date
8-7-2014
Journal
Cell Reports
Volume
8
Issue
3
Inclusive Pages
647-655
DOI
10.1016/j.celrep.2014.06.039
Keywords
Cell Development Disorders, Pervasive--genetics; DNA-Binding Proteins--metabolism; Intellectual Disability--genetics; NF-kappa B--metabolism; Neurons--metabolism; Seizures--genetics
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
APA Citation
Manzini, M. C., Xiong, L., Shaheen, R., Tambunan, D., Di Costanzo, S., Mitisalis, V., & +15 additional authors (2014). CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.. Cell Reports, 8 (3). http://dx.doi.org/10.1016/j.celrep.2014.06.039
Peer Reviewed
1
Open Access
1
Included in
Cell and Developmental Biology Commons, Medical Pharmacology Commons, Medical Physiology Commons, Pharmacology Commons
Comments
Reproduced with permission of Elsevier B.V. Cell Reports.