TAOK2 – Autism Spectrum Disorder

TAOK2 resides within the 16p11.2 microdeletion region and has been implicated in neurodevelopmental disorders, including autism spectrum disorder. Although TAOK2's role in ASD was unclear, murine models and human genetics converge to support its contribution to ASD pathophysiology (PMID:29467497).

Exome and genome sequencing of ASD families identified three unrelated de novo missense variants in TAOK2, including c.1004C>T (p.Ala335Val) in NM_016151.4, each impairing protein stability and variably disrupting kinase activity, dendrite growth, and spine formation (three probands) (PMID:29467497). No additional familial segregation beyond these de novo events has been observed, consistent with an autosomal dominant de novo inheritance model.

Functional assessment in Taok2 heterozygous (Het) and knockout (KO) mice revealed gene dosage–dependent deficits in cognition, anxiety, social interaction, cortical layering, dendrite and synapse formation, and excitatory neurotransmission, mirroring core ASD phenotypes (PMID:29467497). Mechanistically, loss of Taok2 activity led to reduced RhoA activation, and pharmacological enhancement of RhoA signaling rescued synaptic and dendritic phenotypes.

Human cellular assays corroborated murine findings: patient-derived TAOK2 variants compromised kinase function and microtubule dynamics, contributing to disrupted neuronal connectivity. These convergent data delineate haploinsufficiency of TAOK2 via RhoA signaling as a pathogenic mechanism in ASD.

Collectively, three de novo TAOK2 variants with robust animal and cellular model concordance establish a strong gene–disease association. TAOK2 should be considered in diagnostic evaluation of ASD and represents a potential target for RhoA-modulating therapeutic strategies.

References

• Molecular psychiatry • 2019 • Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. PMID:29467497

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