© UniTrento; photo: Matteo Festi
News • Research explores key role of chromatin
Kabuki syndrome: new insights offer hope for therapies
At the root of the rare genetic disorder affecting 1 in 30,000 people is a deficiency in a protein that acts as a protective mechanism for cells against mechanical stress.
The discovery by an international research team, coordinated by Alessio Zippo at the University of Trento and published in The Embo Journal, opens new therapeutic perspectives.
Growth delay, muscle hypotonia, craniofacial abnormalities, cognitive impairment, and heart defects: these are the key manifestations of Kabuki syndrome, a rare genetic disorder affecting 1 in 30,000 newborns. The condition is caused by mutations in a gene (KMT2D) that encodes a protein called MLL4, which is involved in organizing chromatin – the complex of DNA and proteins within the cell nucleus. A promising breakthrough in understanding the disease and its underlying causes comes from research led by the University of Trento (UniTrento), revealing a previously unknown mechanism that links chromatin alterations to defects in the cellular response to mechanical stimuli.
When [the MLL4] protein is less abundant or altered, as in Kabuki syndrome, the nucleus becomes more fragile, making cells more susceptible to nuclear envelope rupture
Alessio Zippo
The study – the result of a four-year effort and a multidisciplinary approach involving international collaboration among research centers specialized in genetic diseases, cell biology, and molecular biology, alongside physicists specializing in photonics, mechanics, and computational modeling – provides a new perspective on the syndrome, including potential therapeutic avenues. It proposes a new paradigm in chromatin biology: for the first time, it identifies the role of chromatin factors (such as the MLL4 protein) in regulating the cell nucleus’s response to mechanical stress and modulating tissue and organ function. Furthermore, the research demonstrates for the first time how altered nuclear mechanics is directly linked to the pathogenesis of Kabuki syndrome, explaining some of its most common clinical manifestations.
The study stems from a collaboration among numerous Italian and international research institutions and universities the University of Trento (with the Department of Cellular, computational and integrative Biology Cibio and the Department of Physics), Fondazione Bruno Kessler (FBK), Italian Institute of Technology (IIT), the Airc Institute of Molecular Oncology, ETH Zurich, the University of Naples Federico II, and the University and Hospital of Montpellier.
The paper features Sarah D’Annunzio as first author, followed by her colleagues from Alessio Zippo’s research group at CIBIO, together with Raffaello Potestio from the Department of Physics. The study analyzes cells as the "mechanical engine of our organism," fundamental to tissue organization. "Cells are subjected to various mechanical stimuli," explains Alessio Zippo, Associate Professor at the Department of Cellular, computational and integrative Biology at the University of Trento. "They are compressed, stretched, and deformed to regulate various physiological functions. To respond to these stresses, the cell nucleus, which safeguards our genetic material, must adapt without losing its structural integrity."
© UniTrento; photo: Matteo Festi
"We have demonstrated," Zippo continues, "that the MLL4 protein not only regulates gene expression but also helps protect the cell nucleus from the mechanical stress to which it is exposed across multiple tissues. In short, MLL4 acts as a protective mechanism and an intranuclear mechanical sensor, enabling the nucleus to respond to cellular stimuli while maintaining its integrity to safeguard the genome. When this protein is less abundant or altered, as in Kabuki syndrome, the nucleus becomes more fragile, making cells more susceptible to nuclear envelope rupture, which causes the activation of the cGAS/STING signaling pathway that can in turn lead to cell death."
The researchers demonstrated that in experimental models of Kabuki syndrome, pharmacological inhibition of this signaling pathway reduces the phenomenon, "suggesting a potential therapeutic strategy for the disease and for other pathologies characterized by nuclear fragility, including certain types of cancer." "The inhibitors," Zippo adds, "act on the signal triggered in response to nuclear rupture, thereby interrupting this cycle."
The research was developed within a collaboration supported by European programs ChromRare (Marie Skłodowska-Curie Actions, coordinated by UniTrento) and ivBM (EIC Pathfinder, focused on Brillouin Microscopy for diagnostics). The work was also made possible thanks to the support of the Italian Kabuki syndrome association (AISK) and its French counterpart, Association syndrome de Kabuki (ASK).
Source: University of Trento
19.08.2026
