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Biology and genetics of EB

Why is research on EB genetics needed?

Understanding what causes EB is the essential first step in being able to being able to treat EB. Studying the biology of EB helps to develop an understanding of how EB causes blistering and skin damage. Studying the genetics reveals the genes involved in making and maintaining healthy skin, and the mistakes (mutations) in these genes which actually cause EB, and how these are inherited.

Despite the complexity of EB, there has been an explosion of knowledge about the genetics of EB over the past 25-30 years.  We now know at least 14 genes that we believe are responsible for all of the main forms of EB, and this has enabled development of ever-better diagnostics, and also for the first time raises the possibility of correcting the genetic mistakes to develop curative therapies.

Even though the main genes associated with EB are probably now known, we certainly don't yet know all the mutations that cause EB (for example, some 20% of people with EB simplex don't yet have their mutation identified, and a similar picture exists for other EB types). Some people have blistering conditions which may in fact be EB, if only we could identify the gene/ mutation. This is an important area of research which DEBRA funds, and new mutations are being identified all the time.

The way that mistakes in the EB-associated genes actually cause EB is still a very active area of research. Genes are translated into skin proteins, and the mistake in the gene is reflected in the protein: these mistakes can interfere with the way the protein works. The protein might be missing completely, be shorter than usual, or have a big or small mistake in an important bit of the protein. This is why, even for the same gene, the type of EB that results can be very different. For example, both dominant dystrophic EB (DDEB) and recessive dystrophic EB are caused by mistakes in the collagen 7 gene, but the mistakes that cause RDEB have a much more severe effect on the ability of the collagen protein to hold the layers of the skin together.

In addition, we now know that there are other genes, known as 'modifier' genes that can affect the particular characteristics, and severity of symptoms, of any particular type of EB. This is why two siblings (sisters or brothers), or parents and children with exactly the same EB mutation might be affected differently. The genetic makeup of a person includes some 25,000 genes as well as the EB genes, and some of these genes can act to make the effects of the EB mutation on the skin either more, or less, severe. DEBRA funds research into identifying modifier genes associated with all forms of EB. It is thought that modifier genes may be a target for drug development which could significantly alleviate the severity of EB symptoms – but first we have to identify and understand these genes.

This is why research into the fundamental genetics and biology of EB is still so important.

Why is it important for someone with EB to know their exact genetic fault?

Not only do some people with EB find it reassuring to know what the cause of their condition is, but knowing the exact mutation can help predict the course of the disease, how best to manage the symptoms and, in some case, allow genetic counselling if they wish. Perhaps most important is that, in most cases, it will be essential for the exact mutation to be known before a person can receive complex treatments using gene therapy, cell therapy, protein therapy, or some drug therapies, which aim to cure or correct the genetic mistake: without knowing the mutation the therapy might be neither effective or safe.

Some current priorities for research into the genetics and biology of EB:

  • Identifying unknown EB mutations and possible other EB-associated genes
  • Understanding the effects of EB mutations and what therapeutic approach might work
  • Identifying 'modifier' genes that affect characteristics and severity of EB