Published on 18.06.2021
Several patients also have immune abnormalities and intestinal inflammation. Following an international collaboration, the teams have identified a mutation in the IPO8 gene that results in a severe form of this disease. This advance, although it concerns a rare disease, could contribute to a better understanding of more frequent vascular and immune pathologies.
A new severe form of conjunctival dysplasia identified
Connective tissue dysplasias such as Marfan syndrome and related syndromes such as Loeys-Dietz and Shprintzen-Goldberg syndromes, affect to varying degrees the organs of the body made up of connective tissue such as blood vessels, the skeleton, tendons, skin and eyes. The most serious complication is the development of life-threatening aortic aneurysms.
The teams have identified twelve patients with a previously unidentified disease combining cardiovascular damage, joint hyperlaxity, and immune system dysregulation. The patients all have in common a mutation of the IPO8 gene, then identified as responsible for this severe form of dysplasia. Researchers and geneticists have shown that this mutation disrupts the TGF-Beta signaling pathway, which is essential for the development and function of connective tissue cells and for the regulation of the immune system, explaining this clinical picture.
Collaborate internationally to accelerate scientific advances
If this breakthrough was possible, it is thanks to an international and multidisciplinary collaboration involving more than forty researchers in eight countries around the world. Each group, with its expertise, patients, and experiences, has made it possible to pool forces, to do interactive science, and thus to go faster, for the benefit of patients and science
Since 2016, several patients with a similar undiagnosed clinical picture have been identified at Institut Imagine and the Angers University Hospital. By sequencing their genomes, the teams have identified the IPO8 mutation. Other patients were then identified through national and international databases such as Gene Matcher, bringing the total number to twelve.
From then on, the teams, and in particular Alban Ziegler and Rémi Duclaux-Loras, continued to collaborate to describe and characterize these patients. In parallel, thanks to the expertise of Filippo Del Bene and Céline Revenu at the Institut de la Vision, an animal study model, the zebrafish, was developed in order to reproduce the genetic mutation and to observe the anomalies found in the patients. Parallel work carried out in the team of Bart Loeys (University of Antwerp, Belgium), a specialist in the TGF-Beta pathway, confirmed the involvement of the IPO8 gene in connective tissue diseases responsible for aortic aneurysms.
Paving the way for new research
This discovery, if it does not allow to date to cure the people who are affected by it, is a first step towards new research. "We are still in a fog about this disease, but now the lights are on in the night and we can move forward," says Professor Bonneau, a geneticist at the University Hospital in Angers. The discovery of this new gene confirms that the TGF-Beta signaling pathway is important for the development of these diseases and that this gene, previously unknown in this pathway, probably has an important role to study in detail. The next step will be to better understand the immune abnormalities in these patients and to try to correct the disease in zebrafish.
More generally, this discovery of a rare form of connective tissue disease could contribute to a better understanding of more common pathologies, particularly vascular ones such as aortic aneurysms, which affect more than 10,000 people per year in France (abdominal and thoracic aortic aneurysms).
Working on a rare disease serves more common diseases such as the occurrence of aortic aneurysms. This new gene is a piece of the puzzle of vascular pathologies. In addition to the environmental factors already known, this genetic factor could allow us to better understand why some people are more affected than others by vascular diseases