Phenotype prediction in dystrophic epidermolysis bullosa

Peter van den Akker,1,2 Ton van Essen,1 Hendri Pas,2 Hans Scheffer,3 Morris Swertz,4 Robert Hofstra,1 Marcel Jonkman2

Departments of 1Genetics and 2Dermatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
3Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands;
4Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

Dystrophic epidermolysis bullosa (DEB) results from mutations (= errors) in the gene (= genetic code) for type VII collagen. This gene is called COL7A1. Type VII collagen is needed to bind the two layers of the skin together. A gene can be compared to a long barcode on an article in the supermarket where each bar represents one DNA molecule. If something is wrong with one of the bars, the scanner at checkout cannot understand the barcode. If something is wrong with one of the DNA molecules (= a mutation), the cells of the body cannot understand the gene. In case of COL7A1: type VII collagen will not be made at all or only in dysfunctioning form and as a result someone gets DEB.
Everybody carries two copies of COL7A1: one from the mother and one from the father. DEB can be inherited in two ways: dominantly (DDEB) or recessively (RDEB). Dominant means that a mutation in one of the two copies of COL7A1 is enough to get DDEB. Recessive means that someone needs a mutation in both copies of COL7A1 to get RDEB. The nature of the mutations that cause DDEB and RDEB is different.


RDEB is usually more severe than DDEB, but there are many subtypes of both. The typical features and disease course of a subtype are collectively called "the phenotype". Newborns with different phenotypes can have a similar presentation. This makes it difficult to determine the exact phenotype in newborns and thus to accurately predict the future course of disease, while this is so important to parents.
In our research, we try to get more insights into the complex processes that collectively determine the phenotype, in order to be able to better predict that phenotype. DNA analysis is of great help here, as mutations are the best predictors of the phenotype. In order to make the information on all COL7A1 mutations and DEB patients ever identified available and easily accessible to everyone, we have built the International Dystrophic Epidermolysis Bullosa Patient Registry ( Mutations found in a patient can be checked online for free against the registry to see what is known about the mutations, which is a great help in clinical practice.

In the peculiar "RDEB-inversa" phenotype, blisters are usually restricted to the trunk and the body folds (axillae, groins, gluteal fold), but there can be severe swallowing difficulties due to esophageal blistering and narrowing. Patients with RDEB-inversa therefore need specific check-ups. We have found that RDEB-inversa is caused by specific mutations in COL7A1, which enables us to correctly predict this phenotype already in newborns with DEB.

Another good predictor of the phenotype is the amount of type VII collagen in a skin biopsy. We have found that RDEB patients who have a very low amount of type VII collagen in their skin do not get the most severe "RDEB-severe generalized" phenotype. They do develop fusion of the fingers and toes (= pseudosyndactyly), but it starts only after the age of 7 years and is not as severe as in "RDEB-severe generalized". We named this phenotype "RDEB-severe generalized with late-onset pseudosyndactyly".

MMP1 is a protein that degrades type VII collagen. Several groups have studied whether MMP1 influences the phenotype in DEB. However, the results were contradictory. We have also studied MMP1, but we could not confirm that MMP1 influences the phenotype in DEB.

Altogether, our work helps to better predict the phenotype and thus the future in children with DEB, which is so important to the parents and the child.

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