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

• Published in: Clinical genetics 2024-10, Vol.106 (4), p.518-524
• Main Authors: Schnur, Rhonda E., Dvořáček, Lukáš, Kalsner, Louisa, Shapiro, Faye L., Grebeňová, Dana, Yanni, Diana, Wasserman, Barry N., Agrawal, Pankaj, Parker, Margaret, Yu, Timothy, Douglas, Jessica, Young, Vanessa, D'Gama, Alissa, Hills, Sonia, Wojcik, Monika, Brownstein, Catherine, Genetti, Casie, Schmith‐Abe, Klaus, Dyer, Lisa M., Antonarakis, Stylianos E., Kuželová, Kateřina
• Format: Article
• Language: English
• Subjects: Angiogenesis; Apoptosis; Cell adhesion; Cell migration; Cell proliferation; Cytoskeleton; Encephalocele; Endothelial cells; Female; GTP-binding protein; Humans; Infant, Newborn; Knobloch syndrome; Male; meningocele; Mutation, Missense - genetics; p21-Activated Kinases - genetics; PAK2; Retinal Degeneration - genetics; Retinal Degeneration - pathology; retinal detachment; Retinal Detachment - congenital; Retinal Detachment - genetics; Retinal Detachment - pathology; retinopathy of prematurity
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14578

The p21‐activated kinase (PAK) family of proteins regulates various processes requiring dynamic cytoskeleton organization such as cell adhesion, migration, proliferation, and apoptosis. Among the six members of the protein family, PAK2 is specifically involved in apoptosis, angiogenesis, or the development of endothelial cells. We report a novel de novo heterozygous missense PAK2 variant, p.(Thr406Met), found in a newborn with clinical manifestations of Knobloch syndrome. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity. Similar findings were described previously for the PAK2 p.(Glu435Lys) variant found in two siblings with proposed Knobloch syndrome type 2 (KNO2). These new variants support the association of PAK2 kinase deficiency with a second, autosomal dominant form of Knobloch syndrome: KNO2. Knobloch syndrome type 1 is caused by biallelic pathogenic variants in COL18A1 leading to collagen XVIII deficiency. Two new kinase‐deficient PAK2 variants associated with Knobloch syndrome phenotype strongly support a second, autosomal dominant form of Knobloch syndrome: KNO2.