Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2

Abstract

Knobloch syndrome is an autosomal recessive phenotype mainly characterized by retinal detachment and encephalocele caused by biallelic pathogenic variants in the COL18A1 gene. However, there are patients clinically diagnosed as Knobloch syndrome with unknown molecular etiology not linked to COL18A1. We studied an historical pedigree (published in 1998) designated as KNO2 (Knobloch type 2 syndrome with intellectual disability, autistic behavior, retinal degeneration, encephalocele). Whole exome sequencing of the two affected siblings and the normal parents resulted in the identification of a PAK2 non-synonymous substitution p.(Glu435Lys) as a causative variant. The variant was monoallelic and apparently de novo in both siblings indicating a likely germline mosaicism in one of the parents; the mosaicism however could not be observed after deep sequencing of blood parental DNA. PAK2 encodes a member of a small group of serine/threonine kinases; these P21-activating kinases (PAKs) are essential in signal transduction and cellular regulation (cytoskeletal dynamics, cell motility, death and survival signaling, and cell cycle progression). Structural analysis of the PAK2 p.(Glu435Lys) variant which is located in the kinase domain of the protein predicts a possible compromise in the kinase activity. Functional analysis of the p.(Glu435Lys) PAK2 variant in transfected HEK293T cells results in a partial loss of the kinase activity. PAK2 has been previously suggested as an autism related gene. Our results show that PAK2 induced phenotypic spectrum is broad and not fully understood. We conclude that the KNO2 syndrome in the studied family is dominant and caused by a deleterious variant in the PAK2 gene.

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

“…Furthermore, even though PAK2 variations are mostly associated with ASD, the number of cases described at present is not sufficient to get a precise idea of the extent of clinical consequences. For example, the PAK2 mutation associated with KNO2 syndrome (Antonarakis et al, 2021) already differs from previous descriptions 10. 3389/fnins.2023.1123784 of PAK2 clinical cases that were exclusively associated with ASD.…”

“…Clinical studies reported ASD in patients bearing PAK2 missense mutations or with PAK2 deletions, causing PAK2 haploinsufficiency (Wang et al, 2018). One missense p.(Glu435Lys) variation was recently identified by exome sequencing in two siblings displaying a Knobloch-like syndrome designated as KNO2 with ID, autistic behavior, retinal degeneration, and encephalocele (Antonarakis et al, 2021).…”

“…The missense PAK2 variations are de novo or inherited (Zhang K. et al, 2022). The newly described PAK2 mutation, responsible for the KNO2 syndrome, is monoallelic and detected in both siblings, indicating a likely germ-line mosaicism in one of the parents (Antonarakis et al, 2021). Whether this variant is responsible for haploinsufficiency is still unknown.…”

Ade novovariant inPAK2detected in an individual with Knobloch type 2 syndrome

“…While many cases of KNO are caused by variants in COL18A1, diagnosed as Knobloch syndrome type 1 (KNO1, MIM:120328), other individuals with clinically diagnosed KNO have been identified who lack variants in this gene. 1 Recently, PAK2 was identified as a candidate gene for autosomal dominant Knobloch syndrome type 2 (KNO2; MIM:618458), which has similar features to KNO1. 1 PAK2 is a member of the p21-activated kinase (PAK) family proteins, which are serine/threonine kinases involved in signal transduction, cytoskeletal dynamics, cell cycle progression, and cell motility.…”

“…1 Recently, PAK2 was identified as a candidate gene for autosomal dominant Knobloch syndrome type 2 (KNO2; MIM:618458), which has similar features to KNO1. 1 PAK2 is a member of the p21-activated kinase (PAK) family proteins, which are serine/threonine kinases involved in signal transduction, cytoskeletal dynamics, cell cycle progression, and cell motility. 2,3 There are two subfamilies of PAK proteins based on structure, regulation, and sequence identity.…”