A novel finding on Kabuki syndrome, a rare genetic disease

Delayed growth, craniofacial dysmorphism, skeletal abnormalities, moderate intellectual disability and, often, congenital heart defects. This is how the Kabuki syndrome manifests itself, a rare genetic disease, which has an incidence of one case in every 30,000 births.

It has a long time since the cause of the disease has been identified: mutations of KMT2D gene codify for MLL4, a protein involved in the regulation of chromatin, which is the complex of proteins and nucleic acids contained in the nucleus of cells. However, research still has a long way to go to identify new therapeutic approaches for ameliorating the pathological conditions affecting Kabuki syndrome patients.

An Italian team has taken a step forward in this direction, involving biological, mathematical, physical and genetic skills from various scientific realities. The research was developed at the CIBIO Department of Cellular, Computational and Integrated Biology of the University of Trento, with the contribution of the Italian Institute of Technology (IIT), the Telethon Institute of Genetics and Medicine (TIGEM) of Pozzuoli (Naples), the University of Naples Federico II, the Institute of High Performance Computing and Networks of the National Research Council of Naples (CNR-ICAR) and the Vita-Salute San Raffaele University of Milan. The project started at the "Romeo and Enrica Invernizzi" National Institute of Molecular Genetics (INGM) Foundation in Milan.

The study opens up new perspectives in the field of rare genetic diseases as it has succeeded in identifying how the structure and mechanical properties of the nucleus are altered in Kabuki syndrome patients. The findings will be published in the scientific journal Nature Genetics.

Alessio Zippo, at the head of the team that conceived the study, explains: "Our research group has reproduced for the first time the onset of Kabuki syndrome in the laboratory. To do this, we used healthy human stem cells and introduced the genetic mutation that we find in patients' cells. By using cutting-edge technologies, we have discovered that the nuclear architecture is compromised due to an altered chromatin compartmentalization".

Furthermore, the study shows that the impaired formation of cartilage and bones derives from the inability of cells to respond to the mechanical signals that normally guide the process.

He continues: &laquoWe have identified and tested a therapy that restores the properties of the cells affected by the mutation, both in vitro and in vivo. It is about the inhibition of ATR, a nuclear protein that acts as a molecular sensor (mechano-sensor) in response to nuclear mechanical stimuli".

The next step will be to better define the therapeutic potential of targeting ATR to restore the functionality of stem cells and therefore the correct formation of cartilage and the appropriate lengthening of the bones in patients affected by the syndrome.