| Title: |
NEDAMSS syndrome-related truncating and missense mutations are associated with aberrant liquid-liquid phase separation of IRF2BPL |
| Authors: |
Marco Dell’Oca; Stefania Boggio Bozzo; Serena Vaglietti; Chiara Marchetti; Chiara Di Luca; Pietro Munarin; Michael Nicoli; Rossella Indellicato; Davide Ravanelli; Giorgia Falanga; Angelo Iannielli; Mirko Luoni; Alessia Loffreda; Valeria Berno; Paolo Bianchini; Sarah Sertic; Antonio Conforti; Shima Rashidiani; Eleonora Aimaretti; Massimo Collino; Ilaria Cecere; Angelo Gallo; Federica Santoro; Diego Brancaccio; Samuele Rosso; Giovanna Di Nardo; Raffaele Pertusio; Federico Cesano; Francisco J. Monje Quiroga; Mirella Ghirardi; Silvestro Roatta; Luca Colnaghi &; Ferdinando Fiumara |
| Contributors: |
M. Dell’Oca; S. Boggio Bozzo; S. Vaglietti; C. Marchetti; C. Di Luca; P. Munarin; M. Nicoli; R. Indellicato; D. Ravanelli; G. Falanga; A. Iannielli; M. Luoni; A. Loffreda; V. Berno; P. Bianchini; S. Sertic; A. Conforti; S. Rashidiani; E. Aimaretti; M. Collino; I. Cecere; A. Gallo; F. Santoro; D. Brancaccio; S. Rosso; G. Di Nardo; R. Pertusio; F. Cesano; F.J. Monje Quiroga; M. Ghirardi; S. Roatta; L. Colnaghi &; F. Fiumara |
| Publication Year: |
2026 |
| Collection: |
The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: |
Settore BIOS-07/A - Biochimica; Settore BIOS-08/A - Biologia molecolare; Settore BIOS-10/A - Biologia cellulare e applicata |
| Description: |
Since 2018, truncating and missense mutations in the IRF2BPL gene have been associated with the neurodevelopmental NEDAMSS syndrome and other IRF2BPL-related disorders. These mutations mainly affect the gene region encoding the central portion of the IRF2BPL protein, whose physiopathological roles are poorly understood. Here we show that this region contains three low-complexity regions (LCR1-3) and a higher-complexity domain (HCD) similar to DNA-binding domains. The polyA/polyQ-rich LCR1, together with an upstream zinc finger domain, drives IRF2BPL liquid-liquid phase separation (LLPS) in both neuronal and non-neuronal cells. Disease-related truncating and missense mutations disrupt the physiological IRF2BPL LLPS in cells, leading to the formation of aberrant cytoplasmic condensates sequestering wild-type IRF2BPL from the nuclear compartment, activating molecular disease mechanisms, i.e., WNT1 upregulation, and altering neuronal cell electrophysiological properties. These findings identify aberrant LLPS as a key biophysical mechanism underlying the nuclear depletion of wild-type IRF2BPL, a fundamental pathogenic alteration underlying NEDAMSS, triggering downstream cellular and molecular disease mechanisms. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41760624; journal:NATURE COMMUNICATIONS; https://hdl.handle.net/2434/1224417 |
| DOI: |
10.1038/s41467-026-69781-7 |
| Availability: |
https://hdl.handle.net/2434/1224417; https://doi.org/10.1038/s41467-026-69781-7 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.33163225 |
| Database: |
BASE |