Neuropathophysiological significance of the c.1449T>C/p.(Tyr64Cys) mutation in the CDC42 gene responsible for Takenouchi-Kosaki syndrome

Biochem Biophys Res Commun. 2020 Sep 3;529(4):1033-1037. doi: 10.1016/j.bbrc.2020.06.104. Epub 2020 Jul 30.


Takenouchi-Kosaki syndrome (TKS) is an autosomal dominant congenital syndrome, of which pathogenesis is not well understood. Recently, a heterozygous mutation c.1449T > C/p.(Tyr64Cys) in the CDC42 gene, encoding a Rho family small GTPase, has been demonstrated to contribute to the TKS clinical features, including developmental delay with intellectual disability (ID). However, specific molecular mechanisms underlying the neuronal pathophysiology of TKS remain largely unknown. In this study, biochemical analyses revealed that the mutation moderately activates Cdc42. In utero electroporation-based acute expression of Cdc42-Y64C in ventricular zone progenitor cells in embryonic mice cerebral cortex resulted in migration defects and cluster formation of excitatory neurons. Expression the mutant in primary cultured hippocampal neurons caused impaired axon elongation. These data suggest that the c.1449T > C/p.(Tyr64Cys) mutation causes altered CDC42 function and results in defects in neuronal morphology and migration during brain development, which is likely to be responsible for pathophysiology of psychomotor delay and ID in TKS.

Keywords: CDC42; Cerebral cortex; Neuron; Small GTPase; Takenouchi-kosaki syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Brain / pathology*
  • Brain / physiopathology*
  • COS Cells
  • Cell Aggregation
  • Cell Movement
  • Cells, Cultured
  • Cerebral Cortex
  • Chlorocebus aethiops
  • Genetic Predisposition to Disease*
  • Hippocampus / pathology
  • Mice, Inbred ICR
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Neurites / metabolism
  • Organogenesis
  • Polymorphism, Single Nucleotide / genetics*
  • Syndrome
  • cdc42 GTP-Binding Protein / genetics*


  • Mutant Proteins
  • cdc42 GTP-Binding Protein