Published on 17.05.2022
Research Acceleration
In biology, structure and function are closely linked. Our intestine is no exception to this rule. The cells of the intestinal wall specialise to form a brush border on their surface (see image). This structure, made up of thousands of membrane folds or "microvilli", contains the transporters necessary to capture nutrients in the intestinal lumen and to control the exchange of water and salts between the organism and the external environment. In certain genetic intestinal diseases, generally grouped under the name of 'microvillous atrophy', there is a defect in the formation of this brush border. "This defect manifests itself from birth in the form of severe diarrhoea leading to severe dehydration and undernutrition," explains Nadine Cerf-Bensussan, director of the Intestinal Immunity Laboratory at the Institut Imagine.
A new gene identified
The most common genetic causes are loss-of-function mutations in the MYO5B gene. This gene codes for a protein, myosin 5B, which enables the transport of various components of the brush border to the apical surface of the intestinal cells. When myosin 5B is mutated, the brush border is disorganised and lacks its transporters, causing very severe diarrhoea.
In a study published on 16 May in The Journal of Clinical Investigation, Nadine Cerf-Bensussan's team identified a new cause for this family of diseases [1]. The team focused on children with severe diarrhoea with no known genetic cause. "To identify the genetic origin of their symptoms, we sequenced the coding parts of their genome - the so-called exome - and identified loss-of-function mutations in the Unc45a gene encoding the Unc45a protein," explains Marianna Parlato, research fellow and last author. Mutations in this gene have very recently been reported in other children with severe diarrhoea, but the mechanism of the diarrhoea is not clear.
UNC45: a key protein in the formation of the intestinal barrier
The published work shows that UNC45 acts as a 'chaperone' for myosin 5B. In practice, it "helps" myosin 5B to fold correctly to have the correct three-dimensional structure. Thus, when Unc45a is mutated and non-functional, myosin 5 loses its structure and becomes unable to perform its function in the development of the brush border of the gut.
This discovery was based on the study of 6 patients and benefited from a collaboration between the Imagine Institute, gastroenterologists from the Necker-Enfants Malades and Robert Debré hospitals at AP-HP and the Ankara Children's Hospital in Turkey, geneticists from the Dijon University Hospital and the University of Oxford, and researchers from the Institut de la Vision, Université Paris-Cité and the University of Innsbruck in Austria. The characterisation of the molecular defect was carried out using a combination of classic approaches (histological and biochemical analyses, electronic microscopy) and innovative approaches in zebrafish or through the use of organoids, a kind of miniature intestine reconstituted in the laboratory from stem cells.
"The same abnormalities in brush border formation and transporter targeting are found in both cell lines, zebrafish and organoids with loss-of-function mutations in Unc45," explain Nadine Cerf-Bensussan and Marianna Parlato. This body of evidence validates the hypothesis that this genetic variant plays a key role in the intestinal barrier defects in these children and provides a better understanding of the mechanisms of intestinal barrier development. The precise discovery of the mechanism responsible for the disease makes it possible to envisage the search for a drug that could correct the myosin 5B folding defect and restore the development of the brush border.