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FB2026_01
,
released March 12, 2026
Two of the three TAOK genes in human have been potentially implicated in neurodevelopmental disorders. These genes encode serine/threonine kinases involved in many different processes including cell signaling, microtubule organization and stability, DNA damage response, and apoptosis. There is a single orthologous gene in Drosophila, Tao, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
In an exome sequencing study of patients with uncharacterized neurodevelopmental disorders, de novo mutations in the MAP kinase kinase TAOK1 were identified in eight carriers. All carriers of these variants have developmental delay in language or motor development, plus a variety of symptoms that were shared by some but not all carriers.
The human MAP kinase kinase gene TAOK2 has been potentially implicated in a number of hereditary neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. See the human disease model report ‘autism spectrum disorder, susceptibility to (postulated), TAOK2-related’ (FBhh0001219). TAOK2 is located within the chromosome16p11.2 deletion; this deletion has been associated with a range of neurodevelopmental disorders, including autism, intellectual disability, and schizophrenia. Genetic interactions of genes within in the chromosome 16p11.2 deletion have been studied using the orthologous genes in flies (see FBhh0001068).
Multiple UAS constructs of the human Hsap\TAOK2 gene have been introduced into flies, including wild-type and variants implicated in autism spectrum disorder (additional information reported in FBhh0001219). Heterologous rescue (functional complementation) has been demonstrated for the abnormal dendritic branching, dynamic microtubule alterations, and behavioral defect phenotypes of Tao mutant animals. Neither of the other two human genes, TAOK1 nor TAOK3, has been introduced into flies.
Phenotypes of Dmel\Tao using RNAi-effected knockdown in different stages and tissues have been extensively characterized. Flies with ubiquitous knockdown of Tao show delayed development and early death, mostly between the third larval instar and pharate adult stage; ventral nerve cords are smaller and less defined, and there are fewer boutons per muscle section at neuromuscular junctions. Knocking down Tao specifically in motor neurons shows decreased mitochondrial size in nerve axons, suggesting an impairment in axonal transport. Tao function appears to be required in developing and as well as adult stages for maintaining normal dendritic arborization and for sensory functions that regulate escape and social behavior. Physical and genetic interactions have been described for Dmel\Tao; see below and in the Tao gene report.
[updated Jul. 2020 by FlyBase; FBrf0222196]
All carriers of TAOK1 variants have developmental delay affecting speech and language development and/or motor development. Other symptoms seen in three or more carriers include muscular hyptonia, intellectual disability, and macrocephaly. (Dulovic-Mahlow et al. 2019, FBrf0242752.)
Neurodevelopmental disorders (NDDs) often arise from pathogenic de novo variants in genes critical for brain development. They are defined as including global developmental delay, seizures, microcephaly, macrocephaly, motor delay, delayed speech and language development, or intellectual disability. As a result of the enormous genetic heterogeneity of these disorders, next-generation sequencing approaches have been effective means of diagnosing individuals with NDDs, but the diagnostic yield is about 50% at best. The molecular diagnosis provides an approach to shifting from a more phenotype-driven management of the symptoms to a more refined treatment based on genotype. (Adapted from Dulovic-Mahlow et al. 2019, FBrf0242752.)
Loss-of-function variants of TAOK2 are postulated to be implicated in autism spectrum disorder (Richter et al., 2018; pubmed:29467497).
TAOK2 is associated with schizophrenia in multiple GWAS studies (see GWAS Catalog, below in 'External links').
TAOs are MAP3Ks in the p38 MAPK cascade that were originally identified based on their kinase domain similarity to the yeast Ste20p MAP4K. TAOs regulate p38 via their ability to phosphorylate and activate the MAPK kinases MEK3 and 6 (Hutchison et al, 1998; Chen et al, 2003). TAOs have been implicated in regulation of cytoskeleton stability, G protein-coupled receptor signaling to p38, activation of p38 after DNA damage, and cell survival. (Adapted from Raman et al. 2007 and references therein, pubmed:17396146.)
Many to one: 3 human genes to 1 Drosophila gene.
Many to one: 3 human genes to 1 Drosophila gene.
High-ranking ortholog of human TAOK1, but also its paralogs TAOK2 and TAOK3.