PAK2 – Knobloch Syndrome Type 2

Knobloch syndrome type 2 (KNO2) is an autosomal dominant developmental disorder characterized by encephalocele, retinal detachment/degeneration, intellectual disability, and autistic behavior. Unlike classical Knobloch syndrome caused by biallelic COL18A1 variants, KNO2 arises from monoallelic pathogenic variants in PAK2, encoding a serine/threonine kinase crucial for cytoskeletal dynamics and cell survival (PMID:33693784).

Genetic evidence includes two affected siblings from a historical pedigree with a de novo PAK2 c.1303G>A (p.Glu435Lys) variant and likely germline mosaicism in a parent (PMID:33693784), a single individual with de novo c.1273G>A (p.Asp425Asn) (PMID:38712026), and a newborn with de novo c.1217C>T (p.Thr406Met) (PMID:38894571). In total, four probands across three unrelated families support a monoallelic, dominant inheritance pattern.

Segregation is limited to concordant genotypes in the two siblings but absent in parents by blood testing, indicating germline mosaicism ([PMID:33693784]). No multigenerational transmission has been observed to date. All variants cluster in the kinase domain and are predicted damaging by in silico modeling.

Functional assays in HEK293T cells demonstrate that p.Glu435Lys and p.Thr406Met markedly reduce PAK2 kinase activity and downstream phosphorylation at activation loop residues (Ser141), consistent with a loss-of-function mechanism ([PMID:33693784]; [PMID:38894571]). Structural analysis predicts compromised ATP binding or substrate recognition in these variants.

There is no conflicting evidence reassigning PAK2 variants to alternative phenotypes in the context of KNO2. While PAK2 has roles in other disorders (e.g., ASD, cancer), the clustering of de novo kinase–deficient variants in KNO2 probands and concordant cellular defects establish specificity for this syndrome.

In summary, monoallelic de novo PAK2 kinase–deficient variants cause autosomal dominant Knobloch syndrome type 2 via a haploinsufficiency or dominant‐negative mechanism. Genetic testing for PAK2 variants informs diagnosis and surveillance for ocular and neurodevelopmental complications.

References

• Human molecular genetics • 2021 • Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2. PMID:33693784
• bioRxiv • 2024 • A de novo variant in PAK2 detected in an individual with Knobloch type 2 syndrome. PMID:38712026
• Clinical genetics • 2024 • New kinase-deficient PAK2 variants associated with Knobloch syndrome type 2. PMID:38894571

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