Rare mutations in the CTTNBP2 gene were originally reported in individuals with autism in Cheung et al., 2001; however, genetic association was not found in this report when allele frequencies were compared to the control cohort. A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Functional analysis of ASD-associated CTTNBP2 variants (originally reported in De Rubeis et al., 2014) in Shih et al., 2020 found that four ASD-associated variants resulted in reduced dendritic spine density in cultured hippocampal neurons; furthermore, mice that were heterozygous for the ASD-associated p.Met121Ile variant (p.Met120Ile in mouse) exhibited reduced dendritic spine density and reduced social interactions. Shih et al., 2022 reported that liquid-liquid phase separation and zinc-induced liquid-to-gel phase transition regulated the synaptic distribution and protein-protein interaction of CTTNBP2, which formed self-assembled condensates throught its C-terminal intrinsically disordered region and facilitated SHANK3 co-condensation at dendritic spines, while zinc was found to bind to CTTNBP2, promoting higher-order assemblies and leading to reduced mobility and enhanced stability and synaptic retention of CTTNBP2 condensates; ASD-linked mutations were subsequently found to alter condensate formation and synaptic retention of CTTNBP2 and impaired mouse social behaviors, which could be ameliorated by zinc supplementation.
Molecular Function
A similar gene in rat interacts with a central regulator of the actin cytoskeleton.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Identification of the human cortactin-binding protein-2 gene from the autism candidate region at 7q31.
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Mice with talen mediated frameshift deletions in exon 3 of the cttnbp2 gene generated by crossing male cttnbp2 het mice with female cttnbp2 het mice. authors previous publication used mouse line 3-1 whereas the current study uses mouse line 1-9 due to higher breeding rate. reporter thy1-eyfp mice (jackson #003782) were crossed to label neurons.
Allele Type: Knockout
Strain of Origin: NA
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 32492416
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Mice with talen mediated frameshift deletions in exon 3 of the cttnbp2 gene generated by crossing male cttnbp2 het mice with female cttnbp2 het mice. authors previous publication used mouse line 3-1 whereas the current study uses mouse line 1-9 due to higher breeding rate. reporter thy1-eyfp mice (jackson #003782) were crossed to label neurons.
Allele Type: Knockout
Strain of Origin: NA
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 32492416
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Mice with the asd-linked r533* mutation in the cttnbp2 gene were generated using crispr/cas9 technology. the asd-linked mutation results in early termination of the cttnbp2 gene, i.e., r536* (corresponding to mouse r533*). mouse r533* truncated proteins lack the c-terminal p-rich domain, i.e., the cortactin binding site.
Allele Type: Knockin (asd mutation)
Strain of Origin: NA
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 32492416
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation r533*, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Multifactorial
Mutation:
Bp2-mir-resistant wt (control) and d570y mutant proteins cotransfected with bp2-mir or control vector ctrl-mir into hippocampal neurons. treatment of hippocampal neurons with knockdown construct bp2-mir reduces endogenous wt cttnbp2 protein.
Allele Type: Multifactorial
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Crispr/cas9 genomic editing technology was used to generate m120i knockin mice. to investigate dendritic spine features mice were crossed with thy1-yfp-h transgenic mice to outline neuronal morphology of forebrain projection neurons.
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Crispr/cas9 genomic editing technology was used to generate d570y knockin mice. to investigate dendritic spine features mice were crossed with thy1-yfp-h transgenic mice to outline neuronal morphology of forebrain projection neurons.
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation m120i located in the n-terminal coiledcoil domain, which is involved in cttnbp2 hetero and homo-oligomerization, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation g342r, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation p353a, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation d570y, in the c-terminal p-rich region, which is required for cortactin interaction, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation r42w, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Paired-nicking crispr/cas9 was used to insert mutant sequences into exon 4 of cttnbp2 bearing the asd mutation a112t, into hippocampal neurons
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33168105
Description: Increased protein levels of levels of shank3, dpysl3, and rac3 in total brain lysates; no change in protein levels of shank2, strn, and mob4 in total brain lysates
Description: Expression of the d570y mutant protein reduced dendritic spine density in bp2-mir-expressing neurons, indicating wt cttnbp2 neutralizes the impact of the d570y mutation
Neuronal activation following behavioral stimulation: c-Fos levels1
Decreased
Description: Decreased neuronal activity in the ca1, ca2 and ca3 regions of hippocampus and basolateral amygdala two hours after reciprocal social interaction test
Description: D570y mutation alters the subcellular distribution of cttnbp2 in neurons; d570y mutant protein was lower around the tips of dendritic spines
