New kinase-deficient PAK2 variants associated with Knobloch syndrome type 2

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• The p21-activated kinase (PAK) family regulates cytoskeleton dynamics, crucial for cell adhesion, migration, proliferation, and apoptosis.
• PAK2 specifically plays roles in apoptosis, angiogenesis, and endothelial cell development.
• Knobloch syndrome is a rare genetic disorder characterized by occipital encephalocele, eye abnormalities, and developmental delay.

Purpose of the Study:

• To investigate the role of PAK2 variants in Knobloch syndrome.
• To identify novel genetic causes for Knobloch syndrome.
• To elucidate the functional consequences of identified PAK2 variants.

Main Methods:

• Genetic sequencing to identify variants in patients with Knobloch syndrome.
• In vitro kinase activity assays to assess the functional impact of PAK2 variants.
• Literature review of previously reported PAK2 variants associated with similar phenotypes.

Main Results:

• A novel de novo heterozygous missense PAK2 variant, p.(Thr406Met), was identified in a newborn with Knobloch syndrome.
• In vitro experiments demonstrated substantially impaired kinase activity for both p.(Thr406Met) and a previously reported variant p.(Asp425Asn).
• These findings are consistent with previously reported PAK2 variants (e.g., p.(Glu435Lys)) associated with a proposed Knobloch syndrome type 2 (KNO2).

Conclusions:

• The identified PAK2 variants support the association of PAK2 kinase deficiency with a second, autosomal dominant form of Knobloch syndrome, designated KNO2.
• PAK2 kinase deficiency is a newly recognized cause of autosomal dominant Knobloch syndrome.
• This study expands the genetic basis of Knobloch syndrome and highlights PAK2's critical role in development.