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Relevance to Autism

CASKIN1 was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were a de novo loss-of-function variant and three damaging de novo missense variants (defined as having a REVEL score > 0.5). Subsequent gene-based meta-analysis involving de novo variant enrichment, transmission disequilibrium testing (TDT) of rare, inherited LoFs from unaffected parents to affected offspring, and comparisons of loss-of-function variants in cases vs population controls in this report found that CASKIN1 exhibited a nominal enrichment of loss-of-function variants in cases vs. controls (p = 0.02). CASKIN1 was also identifeid as an ASD candidate gene based on having a false discovery rate (FDR) < 0.001 following joint analysis of protein-truncating variants, missense variants, and copy number variants in a cohort of 63,237 individuals in Fu et al., 2022. Wilfert et al., 2021 identified two ultra-rare inherited frameshift variants in CASKIN1 that were exclusively transmitted to ASD probands from two independent families. Caskin1-knockout mice were found to exhibit differences in gait, enhanced nociception, anxiety-like behavior, strong freezing responses in contextual and cued-fear conditioning tests, and low memory retention in the Barnes Maze test, suggesting that Caskin1 contributes to a wide spectrum of behavioral phenotypes (Katano et al., 2018).

Molecular Function

Enables identical protein binding activity. Predicted to be involved in signal transduction. Predicted to be active in cytoplasm and membrane. Immunoprecipitation studies in Tabuchi et al., 2002 demonstrated that Caskin1 stably binds to CASK in the brain, while affinity chromatography experiments determined that Caskin1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin-1. Bencsik et al., 2019 found that, In cultured Caskin knockout hippocampal neurons, overexpressed Caskin1 was enriched in dendritic spine heads and increased the amount of mushroom-shaped dendritic spines; furthermore, the authors found that Shank2, a master scaffold of the postsynaptic density, and Caskin1 co-localized within the same complex.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Integrating de novo and inherited variants in 42
ASD
Support
Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins
Support
Distribution of Caskin1 protein and phenotypic characterization of its knockout mice using a comprehensive behavioral test battery
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1
Support
Recent ultra-rare inherited variants implicate new autism candidate risk genes
ASD
Recent Recommendation
Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1350R001 
 synonymous_variant 
 c.1152T>G 
 p.Gly384%3D 
 De novo 
  
  
 GEN1350R002 
 frameshift_variant 
 c.2217del 
 p.Arg740GlyfsTer65 
 De novo 
  
 Simplex 
 GEN1350R003 
 missense_variant 
 c.322G>A 
 p.Val108Met 
 De novo 
  
 Simplex 
 GEN1350R004 
 synonymous_variant 
 c.2778C>T 
 p.Ala926%3D 
 De novo 
  
 Simplex 
 GEN1350R005 
 missense_variant 
 c.4247G>C 
 p.Gly1416Ala 
 De novo 
  
  
 GEN1350R006 
 missense_variant 
 c.2351G>T 
 p.Arg784Leu 
 De novo 
  
  
 GEN1350R007 
 missense_variant 
 c.1333C>T 
 p.Arg445Trp 
 De novo 
  
  
 GEN1350R008 
 missense_variant 
 c.1193G>A 
 p.Arg398Gln 
 De novo 
  
  
 GEN1350R009 
 missense_variant 
 c.758A>G 
 p.Tyr253Cys 
 De novo 
  
  
 GEN1350R010 
 missense_variant 
 c.481G>A 
 p.Val161Ile 
 De novo 
  
  
 GEN1350R011 
 missense_variant 
 c.263A>C 
 p.Tyr88Ser 
 De novo 
  
  
 GEN1350R012 
 frameshift_variant 
 c.1421_1422del 
 p.Ser474Ter 
 Familial 
  
 Simplex 
 GEN1350R013 
 frameshift_variant 
 c.2968del 
 p.Ala990ProfsTer12 
 Familial 
  
 Simplex 
 GEN1350R014 
 missense_variant 
 c.2117C>T 
 p.Ser706Leu 
 Familial 
  
 Multiplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Deletion-Duplication
 68
 
16
Duplication
 3
 
16
Deletion-Duplication
 2
 
16
Deletion
 5
 

Model Summary

Caskin1 knockout mice exhibited abnormal gait, enhanced nociception, and abnormal anxiety-like behavior relative to their wild-type littermates. In addition, the knockouts exhibited an increased freezing response to fear conditioning, with or without a cue tone, in contextual and cued-tests as well as decreased long-term spatial memory retention in the Barnes Maze test.

References

Type
Title
Author, Year
Additional
Distribution of Caskin1 protein and phenotypic characterization of its knockout mice using a comprehensive behavioral test battery
Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Caskin1-floxed mice were produced by using the embryonic stem (ES) cell line RENKA. To yield heterozygous knock-out (Caskin1+/-) mice, Caskin1^flox/+ mice were crossed with TLCN-Cre mice, by which recombination is induced throughout the whole body.
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: RENKA
Mutant ES Cell Line:
Model Source: NIH
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Locomotor activity in diurnal cycle1
Decreased
 Home cage behavior
 3-4 months
Gait1
Abnormal
 Footprint analysis
 3-4 months
Rearing behavior1
Decreased
 Open field test
 3-4 months
General locomotor activity: ambulatory activity1
Increased
 Open field test
 3-4 months
Stereotypy1
Decreased
 Open field test
 3-4 months
Pain or nociception: thermal1
Increased
 Hot plate test
 3-4 months
Pain or nociception: mechanical1
Increased
 Von Frey filament test
 3-4 months
Social interaction1
Decreased
 Home cage behavior
 3-4 months
Core body temperature1
Decreased
 Body temperature measurement
 3-4 months
Size/growth1
Decreased
 Body weight measurement
 3-4 months
Anxiety1
Decreased
 Elevated plus maze test
 3-4 months
Fear response1
Increased
 Fear conditioning test
 3-4 months
Depression1
Decreased
 Forced swim test
 3-4 months
Anxiety1
Abnormal
 Light-dark exploration test
 3-4 months
Cued or contextual fear conditioning: memory of cue: long term recall1
Increased
 Fear conditioning test
 3-4 months
Cued or contextual fear conditioning: Memory of cue1
Increased
 Fear conditioning test
 3-4 months
Cued or contextual fear conditioning: memory of context: long term recall1
Increased
 Fear conditioning test
 3-4 months
Spatial reference memory: long term recall1
Decreased
 Barnes maze test
 3-4 months
Cued or contextual fear conditioning: Memory of context1
Increased
 Fear conditioning test
 3-4 months
Targeted expression1
Decreased
 Western blot
 unreported
Targeted expression1
Decreased
 Immunohistochemistry
 unreported
Mortality/lethality1
 No change
 General observations
 P0
Anxiety1
 No change
 Open field test
 3-4 months
Depression1
 No change
 Tail suspension test
 3-4 months
Cued or contextual fear conditioning1
 No change
 Fear conditioning test
 3-4 months
Spatial learning1
 No change
 Barnes maze test
 3-4 months
Spatial working memory1
 No change
 Barnes maze test
 3-4 months
Grip strength1
 No change
 Grip strength test
 3-4 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 3-4 months
Motor strength and endurance1
 No change
 Wire hang test
 3-4 months
Sensorimotor gating: tactile cue1
 No change
 Prepulse inhibition
 3-4 months
Startle response: acoustic stimulus1
 No change
 Prepulse inhibition
 3-4 months
Social approach1
 No change
 Three-chamber social approach test
 3-4 months
Social interaction1
 No change
 Reciprocal social interaction test
 3-4 months
 Not Reported:

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