PMID- 23236174
OWN - NLM
STAT- MEDLINE
DCOM- 20130221
LR  - 20220311
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 52
DP  - 2012 Dec 26
TI  - Loss of CDKL5 disrupts kinome profile and event-related potentials leading to 
      autistic-like phenotypes in mice.
PG  - 21516-21
LID - 10.1073/pnas.1216988110 [doi]
AB  - Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been 
      identified in neurodevelopmental disorders including atypical Rett syndrome 
      (RTT), autism spectrum disorders (ASDs), and early infantile epileptic 
      encephalopathy. The biological function of CDKL5 and its role in the etiology of 
      these disorders, however, remain unclear. Here we report the development of a 
      unique knockout mouse model of CDKL5-related disorders and demonstrate that mice 
      lacking CDKL5 show autistic-like deficits in social interaction, as well as 
      impairments in motor control and fear memory. Neurophysiological recordings 
      reveal alterations in event-related potentials (ERPs) similar to those observed 
      in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple 
      signal transduction pathways, including the AKT-mammalian target of rapamycin 
      (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 
      regulates signal transduction pathways and mediates autistic-like phenotypes and 
      together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental 
      disorders.
FAU - Wang, I-Ting Judy
AU  - Wang IT
AD  - Department of Genetics, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Allen, Megan
AU  - Allen M
FAU - Goffin, Darren
AU  - Goffin D
FAU - Zhu, Xinjian
AU  - Zhu X
FAU - Fairless, Andrew H
AU  - Fairless AH
FAU - Brodkin, Edward S
AU  - Brodkin ES
FAU - Siegel, Steve J
AU  - Siegel SJ
FAU - Marsh, Eric D
AU  - Marsh ED
FAU - Blendy, Julie A
AU  - Blendy JA
FAU - Zhou, Zhaolan
AU  - Zhou Z
LA  - eng
GR  - MH080718/MH/NIMH NIH HHS/United States
GR  - T32 GM008076/GM/NIGMS NIH HHS/United States
GR  - R01 MH080718/MH/NIMH NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - MH017168/MH/NIMH NIH HHS/United States
GR  - R00 NS058391/NS/NINDS NIH HHS/United States
GR  - K02 NS065975/NS/NINDS NIH HHS/United States
GR  - T32 MH017168/MH/NIMH NIH HHS/United States
GR  - K99 NS058391/NS/NINDS NIH HHS/United States
GR  - NS058391/NS/NINDS NIH HHS/United States
GR  - P30 HD18655/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121210
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Proteome)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDKL5 protein, mouse)
SB  - IM
MH  - Animals
MH  - Anxiety/complications/enzymology/physiopathology
MH  - Autistic Disorder/complications/*enzymology/*physiopathology
MH  - Behavior, Animal
MH  - Electroencephalography
MH  - Evoked Potentials/*physiology
MH  - Hyperkinesis/complications/enzymology/physiopathology
MH  - Memory/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neurons/metabolism/pathology
MH  - Phenotype
MH  - Protein Serine-Threonine Kinases/*deficiency/metabolism
MH  - Proteome/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Seizures/complications/physiopathology
MH  - Signal Transduction
MH  - Social Behavior
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3535652
COIS- The authors declare no conflict of interest.
EDAT- 2012/12/14 06:00
MHDA- 2013/02/22 06:00
PMCR- 2013/06/26
CRDT- 2012/12/14 06:00
PHST- 2012/12/14 06:00 [entrez]
PHST- 2012/12/14 06:00 [pubmed]
PHST- 2013/02/22 06:00 [medline]
PHST- 2013/06/26 00:00 [pmc-release]
AID - 1216988110 [pii]
AID - 201216988 [pii]
AID - 10.1073/pnas.1216988110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21516-21. doi: 
      10.1073/pnas.1216988110. Epub 2012 Dec 10.