p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy

Clin Genet. 2019 Nov;96(5):449-455. doi: 10.1111/cge.13618. Epub 2019 Aug 13.

Abstract

The p21-activated kinase (PAK) family of proteins function as key effectors of RHO family GTPases in mammalian cells to regulate many pathways including Ras/Raf/MEK/ERK and Wnt/β-catenin, amongst others. Here we report an individual with a novel autosomal dominant disorder characterized by severe regressive autism, intellectual disability, and epilepsy. Exome sequencing of the proband and her parents revealed a de novo variant in the PAK1 gene ([NM_001128620] c.362C>T/p.Pro121Leu). Studies in patient cells showed a clear effect on PAK1 protein function, including altered phosphorylation of targets (JNK and ERK), decreased abundance of β-catenin, and concomitant altered expression downstream of these key regulators. Our findings add PAK1 to the list of PAK proteins and kinases which when mutated cause rare genetic diseases.

Keywords: autistic disorder; epilepsy; intellectual disability; p21-activated kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autistic Disorder / genetics*
  • Autistic Disorder / pathology
  • Child
  • Child, Preschool
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Exome Sequencing
  • Female
  • GTP-Binding Proteins / genetics
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Phosphorylation
  • Signal Transduction / genetics
  • p21-Activated Kinases / genetics*

Substances

  • p21-Activated Kinases
  • GTP-Binding Proteins

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