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

Area of Science:

• Cellular biology
• Genetics
• Neuroscience

Background:

• p21-activated kinase (PAK) proteins are crucial effectors of RHO GTPases.
• PAK proteins regulate vital cellular pathways, including Ras/Raf/MEK/ERK and Wnt/β-catenin.
• Dysregulation of these pathways is implicated in various neurological disorders.

Purpose of the Study:

• To identify the genetic cause of a novel autosomal dominant disorder.
• To investigate the functional consequences of a newly identified PAK1 gene variant.
• To understand the molecular mechanisms underlying the observed neurodevelopmental phenotype.

Main Methods:

• Exome sequencing was performed on an affected individual and her parents.
• Patient-derived cells were analyzed to assess PAK1 protein function.
• Phosphorylation status of downstream targets (JNK, ERK) and β-catenin levels were evaluated.

Main Results:

• A de novo variant (c.362C>T/p.Pro121Leu) in the PAK1 gene was identified.
• The identified variant significantly impacted PAK1 protein function in patient cells.
• Altered phosphorylation of JNK and ERK, and decreased β-catenin abundance were observed.

Conclusions:

• The study identifies PAK1 as a novel gene associated with rare genetic diseases.
• Mutations in PAK1 can lead to a syndromic disorder characterized by autism, intellectual disability, and epilepsy.
• This research expands the understanding of PAK protein family's role in human health and disease.