Extending the molecular background of epidermolysis bullosa (EB) - Extension

Short lay summary

This project aims at extending the molecular background of epidermolysis bullosa (EB) by identifying disease-causing mutations in genetically unsolved cases. The team led by Prof. Has reported on a new gene called KLHL24 which when mutated results in a new subtype of EBS. They have also identified new mutational mechanisms in already known EB genes. Little is known about the protein KLHL24, but it seems to be necessary to maintain the balance between intermediate filament stability and degradation. This process is important for skin integrity, and essentially controls the levels of keratin 14 during the differentiation of keratinocytes. This research project seeks to analyse in more detail the mutational background as well as the clinical features and natural history of this EBS subtype. It also aims to establish the physiological role of KLHL24 in the skin further.

Scientific summary

The proposed additional research aims at a better understanding of EBS caused by KLHL24 mutations. We will build on the achieved experience and tools and focus on two questions. Which is the spectrum of mutations and clinical features of this EBS subtype? We will extend the cohort of patients, analyse the mutational background and describe the clinical features and natural history.

Which is the role of KLHL24 in the skin? The physiological role of KLHL24 will be studied in more detail, as well as the existence of additional substrates or functions in keratinocytes and fibroblasts.

Strategic relevance

The detection of genomic variants underlying the various forms of EB facilitates accurate diagnosis, classification and prognosis, and helps monitor the response to therapy. Molecular diagnostics and genetic studies identify genomic biomarkers that not only allow physicians to assess a person’s predisposition to EB but also provide invaluable insights into the pathomechanisms of the disease. These genetic biomarkers are crucial in the stratification of patients, which lies at the base of any attempt at designing and implementing individual treatment modalities. Moreover, we found that EBS patients with KLHL24 mutations develop dilated cardiomyopathy in early adulthood. This finding is of crucial relevance for the prognosis, and for management. Patients require regular cardiologic screening for early diagnosis and therapy.