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.

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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.

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