In a genome-wide study, association was found between CNVs in the COP1 gene (formerly known as the RFWD2 gene) and autism in AGRE and ACC cohorts (European ancestry) (Glessner et al., 2009).
Molecular Function
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
There are ASD probands that carry three copies of the COP1 gene, which encodes an E3 ubiquitin ligase. An ASD mouse model that also carries three copies of the COP1 gene exhibits core symptoms of autism. Male mutant mice show deficits in social behavior, decreased ultrasonic communication, increased repetitive behavior, increased anxiety and decreased spatial memory, whereas female mutant mice show subtle deficits in social communication and spatial memory but no significant changes in anxiety-like, repetitive, and social behaviors. Behavioral phenotypes are accompanied by neurophysiological phenotypes, such as reduced dendritic spine density and decreased excitatory synaptic transmission in the prelimbic area of the medial prefrontal cortex. Core behavioral phenotypes are rescued by overexpression of ETV5, a major substrate of COP1.
References
Type
Title
Author, Year
Primary
Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice
Model Type:
Genetic
Model Genotype:
Transgenic heterozygous
Mutation:
A CAG-loxP-STOP-loxP-Cop1 cDNA-WPRE-polyA cassette is introduced into intron between exons 1 and 2 of the ROSA26 locus by CRISPR/cas9 methodologies. Cre-mediated recombination removes the STOP, to express Cop1. Mice with the knockin allele were crossed with mice carrying the Syn1-cre transgene, where Cre recombinase expression is driven by the Synapsin 1 promoter. Cre-expressing heterozygous Cop1 knockin mutant mice express three copies of Cop1 in cells that express Synapsin 1 (neurons).
Allele Type: Conditional overexpression
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Not reported
Mutant ES Cell Line: Model Source: Biocytogen
Model Type:
Genetic
Model Genotype:
Transgenic homozygous
Mutation:
A CAG-loxP-STOP-loxP-Cop1 cDNA-WPRE-polyA cassette is introduced into intron between exons 1 and 2 of the ROSA26 locus by CRISPR/cas9 methodologies. Cre-mediated recombination removes the STOP, to express Cop1. Mice with the knockin allele were crossed with mice carrying the Syn1-cre transgene, where Cre recombinase expression is driven by the Synapsin 1 promoter. Cre-expressing homozygous Cop1 knockin mutant mice express four copies of Cop1 in cells that express Synapsin 1 (neurons).
Allele Type: Conditional overexpression
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Not reported
Mutant ES Cell Line: Model Source: Biocytogen
Description: Total spine density (thin, stubby, and mushroom) and mushroom spine number were significantly reduced on the apical dendrites of prelimbic layer II/III pyramidal neurons of mutant male mice compared to those of wildtype littermates.
Description: Amplitude of evoked excitatory postsynaptic currents is decreased in the prelimbic layer II/III recordings from cortical acute slices from mutant male mice compared to wildtypes.
Description: Male mutant and wildtype mice spent more time with the novel mouse than with the empty chamber, but mutant mice show a significant decrease in the preference index for novel mouse compared to wildtype littermates.
Description: While wildtype littermates show more interaction with the novel mouse than with the familiar mouse, mutant mice spend the same amount of time interacting with both mice, as a result mutant mice show a significant decrease in the preference index for the novel mouse compared to wildtype littermates.
Description: Male mutant mice show a decreased in number of calls and total call duration at P5, P7 and P9, and a decrease in individual call duration at P5. Female mutant mice show a decrease in individual call duration at P5.
Description: During the probe trials, mutant male mice showed significant deficits in spatial memory as evidenced by an increase in escape latency in locating the target hole, an increase in exploration errors, and decreased time spent in the target quadrant. Female mutant mice showed a smaller deficit in spatial memory as evidenced by an increase in escape latency to locate the target hole on day 6, but not on day 9.
Description: Male and female mutant mice show decreased ETV5 expression in the medial prefrontal cortes.PSD95 protein levels are unchanged in male mice.
Exp Paradigm: ETV5
Description: RFWD2 (COP1) protein levels were increased in the nucleus accumbens, medial prefrontal cortex, hippocampus, and hypothalamus of mutant mice compared to wildtype littermates.
