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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)445-459
Number of pages15
JournalHuman mutation
Volume42
Issue number4
DOIs
StatePublished - Apr 2021
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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