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Thousand and one amino acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase (MAPK) pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function, and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function, and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties and growth problems. This article is protected by copyright. All rights reserved.

Original publication

DOI

10.1002/humu.24176

Type

Journal article

Journal

Hum Mutat

Publication Date

10/02/2021

Keywords

TAOK1, cortical development, functional genomics, in utero electroporation, neurodevelopmental disorders