| Create Account | login

login

Publication

A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic
Transmission, and Causes ASD-Related Behaviors.

Authors	Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ
Submitted By	Submitted Externally on 3/30/2017
Status	Published
Journal	The Journal of neuroscience : the official journal of the Society for Neuroscience
Year	2017
Date Published	2/1/2017
Volume : Pages	37 : 2216 - 2233
PubMed Reference	28130356
Abstract	Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIa catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIa substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIa-WT autophosphorylation. The E183V mutation also reduces CaMKIIa binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIa turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIa targeting to dendritic spines. Moreover, neuronal expression of CaMKIIa-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIa-E183V mutation have lower total forebrain CaMKIIa levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIa-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIa plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes.SIGNIFICANCE STATEMENT Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIa linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.

Back to Top

Store Credentials?

MMPC-Live web resource – Terms of Use

Warranty disclaimer and copyright notice

THE MMPC-Live MAKES NO REPRESENTATION ABOUT THE SUITABILITY OR ACCURACY OF THE SOFTWARE OR DATA FOR ANY PURPOSE, AND MAKES NO WARRANTIES, EITHER EXPRESS OR IMPLIED, INCLUDING MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR THAT THE USE OF THE SOFTWARE OR DATA WILL NOT INFRINGE ANY THIRD PARTY PATENTS, COPYRIGHTS, TRADEMARKS, OR OTHER RIGHTS. THE SOFTWARE AND DATA ARE PROVIDED "AS IS".

The Mouse Metabolic Phenotyping Centers (MMPC-Live) is an NIDDK funded consortium and adheres to the NIH Data Sharing Policy.

MMPC-Live clients make their data freely available whereby MMPC-Live users may freely build upon, enhance and reuse those data for any purpose without restriction. Scholarly citation norms must be followed for content reuse. Please acknowledge the MMPC-Live using the following text: 'The MMPC-Live data used in this manuscript was supported by the NIDDK National Mouse Metabolic Phenotyping Centers (MMPC-Live, RRID:SCR_008997, www.mmpc.org)'. To cite specific MMPC-Live centers, please use the appropriate RRID available from the MMPC-Live website (https://www.mmpc.org/shared/centers.aspx).

Please note that the acknowledgment text includes a Research Resource Identifier (RRID) for the MMPC-Live CU and Centers. Reproducibility is one of the corner stones of effective, open and transparent biomedical published research. However, too often, resources (e.g. model organisms, antibodies, and tools) are not reported with adequate detail to ensure others can replicate or expand upon the published results. The Research Resource Identification Initiative (#RII) seeks to change these limitations in reporting by the use of unique Research Resource Identifiers (RRIDs). This initiative is designed to encourage authors to provide identification of the types of resources used in their research by adding a globally unique accession number to the resources described in the their manuscripts. These identifiers, called RRIDs, will allow authors to cite the resources that they use in their manuscripts. RRIDs allow for easy tracking of all papers that have used the same resource making it easy to access how the same resources works in other scenarios.

It is expected that MMPC-Live users follow scholarly citation norms, giving credit to fellow scholars when accessing/using protocols and data, including data derived by MMPC-Live (such as summary data) and any plots, tables or screenshots depicting those data.

It is possible for invalid or incomplete results to be presented on the MMPC-Live web site due to software bugs, data problems, or artifacts of human error. Data sets are not necessarily static; we reserve the right to post corrections and updates as needed.

Prohibited use. Data contributors and data users may not use MMPC-Live in any unlawful manner, or in any manner that could impair MMPC-Live services, security or functionality. Automated usage (webcrawlers and similar) must observe each page's "meta robots" html tags and space requests by ≥ 2 seconds. We reserve the right to block any IP associated with what we consider to be excessive or abusive usage patterns, and/or to take any action we deem necessary.

MMPC-Live is a National Institutes of Health-sponsored resource that provides experimental testing services to scientists studying diabetes, obesity, diabetic complications, and other metabolic diseases in mice.

Menu

Home

Contact

About MMPC

Animal Husbandry

Tests Data

Search Data

Analysis

Clients

MMPC Centers

Newsletter

Interested in receiving MMPC News?

Mouse Phenotyping
@NationalMMPC

2017 National MMPC. All Rights Reserved.