2. Academic Validation
  3. TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development

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

  • Hum Mutat. 2021 Apr;42(4):445-459. doi: 10.1002/humu.24176.
Geeske M van Woerden 1 2 3,  Melanie Bos 4,  Charlotte de Konink 1,  Ben Distel 1 2 5,  Rossella Avagliano Trezza 1,  Natasha E Shur 6,  Kristin Barañano 7,  Sonal Mahida 7,  Anna Chassevent 7,  Allison Schreiber 8,  Angelika L Erwin 8,  Karen W Gripp 9,  Fatima Rehman 1,  Saskia Brulleman 1,  Róisín McCormack 1,  Gwynna de Geus 1,  Louisa Kalsner 10,  Arthur Sorlin 11 12 13,  Ange-Line Bruel 11 12 13,  David A Koolen 4,  Melissa K Gabriel 14,  Mari Rossi 14,  David R Fitzpatrick 15,  Andrew O M Wilkie 16 17,  Eduardo Calpena 16,  David Johnson 17,  Alice Brooks 3,  Marjon van Slegtenhorst 3,  Julie Fleischer 18,  Daniel Groepper 18,  Kristin Lindstrom 19,  A Micheil Innes 20,  Allison Goodwin 21,  Jennifer Humberson 22,  Amanda Noyes 23,  Katherine G Langley 23,  Aida Telegrafi 23,  Amy Blevins 23,  Jessica Hoffman 23,  Maria J Guillen Sacoto 23,  Jane Juusola 23,  Kristin G Monaghan 23,  Sumit Punj 23,  Marleen Simon 24,  Rolph Pfundt 4,  Ype Elgersma 1 2,  Tjitske Kleefstra 4
Affiliations

Affiliations

  • 1 Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
  • 2 The ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, Rotterdam, The Netherlands.
  • 3 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
  • 4 Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
  • 5 Department of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 6 Division of Genetics and Metabolism, Rare Disease Institute, Children's National Medical Center, Washington, District of Columbia, USA.
  • 7 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
  • 8 Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • 9 Division of Medical Genetics, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
  • 10 Departments of Neurology and Pediatrics, Connecticut Children's Medical Center and University of Connecticut School of Medicine, Farmington, Connecticut, USA.
  • 11 UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • 12 Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  • 13 Centre de Référence maladies rares «Anomalies du Développement et syndromes malformatifs», Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  • 14 Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, California, USA.
  • 15 MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, UK.
  • 16 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 17 Oxford Craniofacial Unit, Oxford University Hospital NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
  • 18 Department of Pediatrics, SIU School of Medicine, Springfield, Illinois, USA.
  • 19 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, USA.
  • 20 Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 21 VCU Medical Center, Clinical Genetics Services, Richmond, Virginia, USA.
  • 22 Division of Pediatric Genetics, Department of Pediatrics, University of Virginia Medical Center, Charlottesville, Virginia, USA.
  • 23 GeneDx, Gaithersburg, Maryland, USA.
  • 24 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
PMID: 33565190 DOI: 10.1002/humu.24176
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.

Keywords

TAOK1; cortical development; functional genomics; in utero electroporation; neurodevelopmental disorders.

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