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Relevance to Autism

TAOK2 resides within the 16p11.2 microdeletion/microduplication region; deletions and duplications in this region are strongly associated with neurodevelopmental disorders, including ASD. A de novo loss-of-function (LoF) variant in the TAOK2 gene was identified in an ASD proband from a multiplex family in Yuen et al., 2017, while a second LoF variant in this gene was identified in another ASD proband in Lim et al., 2017. Taok2 heterozygous and knockout mice were found to display gene dosage-dependent impairments in cognition, anxiety, and social interaction, as well as dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reducted excitatory neurotransmission (Richter et al., 2018). Richter et al., 2018 also reported TAOK2 genetic variants identified by whole-genome and -exome sequencing of over 2600 families with ASD, including two de novo likely gene-disruptive variants [a missense variant (p.Ala135Pro) that was experimentally shown to display reduced kinase activity and alter dendrite growth and spine/synapse development, as well as a splice-site variant] in simplex families. Scharrenberg et al., 2022 showed that overexpression of TAOK2 with ASD-associated variants disrupted neuronal migration in an isoform-specific manner, neurons lacking Taok2 had unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1, mice lacking Taok2 developed gross cortical and cortex layering abnormalities, and acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice.

Molecular Function

This gene encodes a serine/threonine protein kinase that is involved in many different processes, including, cell signaling, microtubule organization and stability, and apoptosis.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
TAOK2 is an ER-localized kinase that catalyzes the dynamic tethering of ER to microtubules
Support
Conserved Tao Kinase Activity Regulates Dendritic Arborization, Cytoskeletal Dynamics, and Sensory Function in Drosophila
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
TAOK2 Kinase Mediates PSD95 Stability and Dendritic Spine Maturation through Septin7 Phosphorylation.
Support
Autism spectrum disorder susceptibility gene TAOK2 affects basal dendrite formation in the neocortex.
Recent Recommendation
Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling.
ASD
Recent Recommendation
TAOK2 rescues autism-linked developmental deficits in a 16p11.2 microdeletion mouse model
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1006R001 
 frameshift_variant 
 TGGGCCCCCCTGCTGCCGCGGTGCCC>T 
 p.Pro1022Ter 
 De novo 
  
 Multiplex 
 GEN1006R002 
 stop_gained 
 c.1162G>T 
 p.Glu388Ter 
 De novo 
  
 Simplex 
 GEN1006R003 
 missense_variant 
 c.403G>C 
 p.Ala135Pro 
 De novo 
  
 Simplex 
 GEN1006R004 
 splice_site_variant 
 c.563+12_563+15del 
  
 De novo 
  
 Simplex 
 GEN1006R005 
 frameshift_variant 
 c.2749del 
 p.Leu917TrpfsTer3 
 Familial 
 Paternal 
 Multiplex 
 GEN1006R006 
 frameshift_variant 
 c.1811_1865del 
 p.Thr604SerfsTer45 
 Unknown 
  
 Simplex 
 GEN1006R007 
 stop_gained 
 c.1864C>T 
 p.Gln622Ter 
 Unknown 
  
 Simplex 
 GEN1006R008 
 missense_variant 
 c.1004C>T 
 p.Ala335Val 
 Familial 
 Paternal 
  
 GEN1006R009 
 missense_variant 
 c.1466G>A 
 p.Arg489Gln 
 Familial 
 Paternal 
 Multiplex 
 GEN1006R010 
 missense_variant 
 c.2233-96C>T 
  
 Familial 
 Paternal 
  
 GEN1006R011 
 missense_variant 
 c.2233-66G>A 
  
 Familial 
 Paternal 
  
 GEN1006R012 
 missense_variant 
 c.2474G>A 
 p.Cys825Tyr 
 Familial 
 Paternal 
  
 GEN1006R013 
 missense_variant 
 c.2512C>A 
 p.Leu838Ile 
 Familial 
 Paternal 
 Simplex 
 GEN1006R014 
 missense_variant 
 c.2987G>A 
 p.Arg996Gln 
 Familial 
 Maternal 
  
 GEN1006R015 
 missense_variant 
 c.3001C>G 
 p.Leu1001Val 
 Familial 
 Maternal 
 Multiplex 
 GEN1006R016 
 missense_variant 
 c.3046G>A 
 p.Val1016Ile 
 Familial 
 Maternal 
 Multiplex 
 GEN1006R017 
 missense_variant 
 c.3337C>T 
 p.Arg1113Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN1006R018 
 missense_variant 
 c.3355C>A 
 p.Pro1119Thr 
 Familial 
 Maternal 
 Multiplex 
 GEN1006R019 
 missense_variant 
 c.2342A>G 
 p.Glu781Gly 
 Familial 
 Maternal 
  
 GEN1006R020 
 missense_variant 
  
  
 Unknown 
  
  
 GEN1006R021 
 missense_variant 
  
  
 Familial 
 Paternal 
  
 GEN1006R022 
 missense_variant 
 c.2609G>A 
 p.Trp870Ter 
 Familial 
 Maternal 
  
 GEN1006R023 
 missense_variant 
  
  
 Familial 
 Maternal 
  
 GEN1006R024 
 missense_variant 
  
  
 Unknown 
 Not maternal 
  
 GEN1006R025 
 missense_variant 
  
  
 Familial 
 Maternal 
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Deletion-Duplication
 139
  construct
16
Duplication
 4
 
16
Deletion
 1
 
16
Deletion
 1
 
16
Duplication
 15
 

Model Summary

Ubiquitous knockdown of Tao results in increased pupal lethality and developmental gross defects. Tissue-specific knockdown results in abnormal eye morphogenesis, abnormal wing development, and increased dendritic tree complexity.

References

Type
Title
Author, Year
Primary
Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster.
Model Type: Genetic
Model Genotype: Transgenic
Mutation: Ubiquitous knockdown of Tao was generated using RNAi transgenic line on medium at 25C degrees.
Allele Type: Knockdown
Strain of Origin: Unreported
Genetic Background: Unreported
ES Cell Line:
Mutant ES Cell Line:
Model Source: VDRC 17432
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Mortality/lethality: pupal1
Increased
 Survival analysis
 Pupae
Appendage development: wing development1
 No change
 Microscopic analysis
 Unreported
Developmental trajectory1
 No change
 General observations
 Unreported
Eye development: compound eye morphogenesis1
 No change
 Microscopic analysis
 Larvae
Mortality/lethality: larval1
 No change
 Survival analysis
 Larvae
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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