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Epigenetic modifiers of disease phenotypes: epidermolysis bullosa as a paradigm (Sprecher 1)

Project lead Prof Eli Sprecher
Organisation Tel Aviv Sourasky Medical Center, Tel Aviv, ISRAEL
Partner organizations & collaborators Assoc. Prof. Verena Wally and Assoc. Prof. Ulrich Koller, both group leaders at the EB House, Austria; Assoc. Prof. Ruby Shalom-Feuerstein, stem cell biologist at the Technion, Israel
Project budget EUR 112,758.00
Start date / Duration 01. Oct 2021 / 36 months
Funder(s) / Co-Funder(s) DEBRA Austria, MSAP/EBEP Recommended
Research area EB genetics, epigenetics & biology

Project details

Short lay summary

Monogenic diseases often feature highly variable phenotypes, despite a usually well-defined genetic cause of the disease. Modifier genes and epigenetic mechanisms are believed to influence phenotypic expressivity. In the rare hereditary skin disorder epidermolysis bullosa (EB), mutations affecting structural proteins necessary for stable attachment of the epidermis to the dermis, lead to skin fragility. Clinical divergence between patients complicate diagnosis and genetic counseling, which emphasizes the need to understand the molecular mechanisms underlying phenotypic variability. In this project we will investigate how genetic/epigenetic mechanisms modulate phenotypic expression in EB.  Should this project be successful, it will ultimately impact on our ability to provide effective patient care while identifying novel actionable drug targets.

Scientific summary

Monogenic diseases often display highly variable phenotypes, despite the fact they are caused by single genetic variants in a well-defined gene. Even siblings carrying the same mutation, occasionally display extremely divergent phenotypes. This divergence is often hypothesized to result from genetic modifiers or epigenetic mechanisms that influence disease manifestations. Here we propose to study this phenomenon in epidermolysis bullosa (EB), a group of monogenic disorders resulting in skin fragility due to genetic variants affecting genes encoding diverse components of the basement membrane. We have collected preliminary evidence pointing at the importance of the contribution of genetic and epigenetic modifier mechanisms to phenotypic expression in EB. Our goal in this project is to identify such modifiers and their mechanism of action. We will focus on two such processes, namely DNA methylation and miRNA regulation of gene expression. The profiles obtained from such analyses will be used to: (1) uncover the epigenetic basis of phenotypic expressivity in EB; (2) model the contribution of epigenetic processes to EB phenotype expressivity. Should this project be successful, it is likely to significantly broaden our understanding of disease pathogenesis and clinical manifestations as well as lead to innovative approaches to EB diagnosis and treatment. Indeed, the systematic characterization of disease-causing epigenetic elements is likely to lead to the delineation of novel biomarkers, actionable drug targets and novel therapeutic strategies to improve disease management.

Strategic relevance

Understanding the molecular basis of a disease through the direct study of patients is expected to yield important information that will be of direct clinical relevance by ultimately helping to improve the quality of genetic counselling, molecular diagnosis, prognostic accuracy, and eventually personalized therapies.


Epidermolysis bullosa
Monogenic diseases
Tel Aviv Sourasky Medical Center
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