Dataset Information

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

ABSTRACT: Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase 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.

SUBMITTER: van Woerden GM

PROVIDER: S-EPMC8248425 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

van Woerden Geeske M GM Bos Melanie M de Konink Charlotte C Distel Ben B Avagliano Trezza Rossella R Shur Natasha E NE Barañano Kristin K Mahida Sonal S Chassevent Anna A Schreiber Allison A Erwin Angelika L AL Gripp Karen W KW Rehman Fatima F Brulleman Saskia S McCormack Róisín R de Geus Gwynna G Kalsner Louisa L Sorlin Arthur A Bruel Ange-Line AL Koolen David A DA Gabriel Melissa K MK Rossi Mari M Fitzpatrick David R DR Wilkie Andrew O M AOM Calpena Eduardo E Johnson David D Brooks Alice A van Slegtenhorst Marjon M Fleischer Julie J Groepper Daniel D Lindstrom Kristin K Innes A Micheil AM Goodwin Allison A Humberson Jennifer J Noyes Amanda A Langley Katherine G KG Telegrafi Aida A Blevins Amy A Hoffman Jessica J Guillen Sacoto Maria J MJ Juusola Jane J Monaghan Kristin G KG Punj Sumit S Simon Marleen M Pfundt Rolph R Elgersma Ype Y Kleefstra Tjitske T

Human mutation 20210301 4

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase 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 f ...[more]

PMID: 33565190

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Project description:Purpose: MBD5-Associated Neurodevelopmental Disorder (MAND) is an Autism Spectrum Disorder (ASD) disorder characterized by intellectual disability, motor delay, severe speech impairment and autism-like behavioral problems. The role of MBD5 in neurodevelopmental function remains largely undefined. In this study, we explored the neurodevelopmental phenotype of 2q23.1 deletion syndrome through creating neuronal progenitor stem cells (NPC) derived from 2q23.1 patients and conducting RNA-seq to identify the contributory altered gene and to expand our knowledge about gene network differences and possible interactions between the related disease pathways and ASD. Methods: Primary skin fibroblasts from three MAND patients and four control cases were converted into induced pluripotent stem cell (iPSC) lines by transient transfections of episomal plasmids. Directed differentiation of these iPSC to NPC was accomplished with monolayer culture protocol for two weeks. Results: The RNA-seq analysis identified 498 genome-wide significant (q < 0.05) differentially expressed gene in the patients derived NPC lines as a consequence of reduced MBD5 dosage. 25 ASD associated genes were included in the differentially expressed gene list. On the top of the list, FOXG1 expression is significantly (P < 0.0001) increased in the patient derived NPC samples. The differentially expressed gene list was highly overlapped with the SFARI autism gene set, identifying biological processes that are implicating neurological phenotype and ASD such as central nervous system development, neuron differentiation, and regulation of neurogenesis. The findings of the transcriptome deviation in early neuronal stage of MAND can provide potential connection to the overlapping neurocognitive and neuropsychiatric phenotypes associated with growing risk factors, such as other chromatin modifiers and epigenetic factors that link to ASD. Such in vitro models can nurture hypotheses toward therapeutic interventions.

Dataset Information

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

Publications

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

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