PACS ‐1 unlocked: How a single mutation disrupts intramolecular regulation to drive neurodevelopmental disease

2026/06/16 by Nadia Izadi‐Pruneyre · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Genomics and Rare Diseases #Hereditary Neurological Disorders #Protein Tyrosine Phosphatases

paper · doi:10.1111/febs.70613

openalex publication_date 2026/06/16 · openalex created_date 2026/06/18 · openalex updated_date 2026/07/22

Abstract

Rare monogenic disorders provide powerful insights into fundamental cell biology. PACS1 syndrome is a striking example of this: a neurodevelopmental disorder, caused almost exclusively by a single missense mutation in the PACS1 gene (c.607C>T), resulting in the Arg203Trp (R203W) amino-acid substitution. Despite the relative genetic simplicity, the exact molecular mechanism through which this mutation drives disease remains unknown. In their study published in this issue of The FEBS Journal, Krzysiak et al. provide a compelling mechanistic framework, demonstrating that the R203W substitution disrupts intramolecular regulation of PACS-1, thereby impairing a critical signalling hub.

Citations

• Bonds and Bytes: the Odyssey of Structural Biology
• Bonds and bytes: The odyssey of structural biology

Discussions

• 📣 My commentary on the insightful paper from the Gronenborn’s lab which demonstrates how a single mutation drives neurodevelopmental diseases doi.org/10.1111/febs... The original paper 👉https://doi. [bsky, 2 points, 0 comments]

Related

• Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy
• Loss of function of VCP/TER94 causes neurodegeneration
• Neurogenetic disorders associated with mutations in the FERRY complex: a novel disease class?
• A hit for base editing: treatment of developmental epilepsy in a mouse model
• Mutations in GFAP Alter Early Lineage Commitment of Organoids