NEDAMSS syndrome-related truncating and missense mutations are associated with aberrant liquid-liquid phase separation of IRF2BPL
Summary
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. © 2026. The Author(s).
| Authors | Dell'Oca M, Boggio Bozzo S, Vaglietti S, Marchetti C, Di Luca C, Munarin P, Nicoli M, Indellicato R, Ravanelli D, Falanga G, Iannielli A, Luoni M, Loffreda A, Berno V, Bianchini P, Sertic S, Conforti A, Rashidiani S, Aimaretti E, Collino M, Cecere I, Gallo A, Santoro F, Brancaccio D, Rosso S, Di Nardo G, Pertusio R, Cesano F, Monje Quiroga FJ, Ghirardi M, Roatta S, Colnaghi L, Fiumara F |
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| Journal | Nature communications |
| Publication Date | 2026 Feb 27;17(1) |
| PubMed | 41760624 |
| PubMed Central | PMC13066210 |
| DOI | 10.1038/s41467-026-69781-7 |