Publication: K14 degradation and ageing in epidermolysis bullosa simplex due to KLHL24 gain-of-function mutations

The study by Mathilde Vermeer et al., published ahead of print in the Journal of Investigative Dermatology, shows that genetic mutations that lead to a hyperactive KLHL24 protein, cause more increased levels of keratin 14 degradation in fetal-like compared to adult-like skin cells. This observation fits with the most severe skin phenotype at a very young age, known as aplasia cutis, congenita. The skin fragility quickly improves within the first years of life and patients only display mild symptoms of skin fragility during adulthood. However, during adolescence patients become at risk to develop a severe form of dilated cardiomyopathy. This study is part of an ongoing collaboration between the department of dermatology (Marieke Bolling) and cardiology (Herman Silljé and principle investigator Peter van der Meer).

The combination of blistering disease with cardiomyopathy

In 2016, hyperactivity of the protein KLHL24 was found to be a new cause of congenital blistering disease, where loss of keratin 14 leads to skin blisters. Last year, the same group showed that patients with hyperactivity of KLHL24, also display desmin deficiency in the heart, causing a severe form of dilated cardiomyopathy. Desmin and keratins are important proteins in heart and skin, respectively, that act as a compliance network to prevent tissue deformations. Loss of these proteins cause dilatation of the heart or blistering of the skin, known as epidermolysis bullosa simplex.

To investigate the skin phenotype of patients, skin biopsies can be obtained. However, in previous studies, a reduction of keratin 14 was not observed in most patients’ skin. As these skin cells have the same intrinsic age as the donor, they may have aged beyond a noticeable detection. Indeed, as the severity of the KLHL24-skin disease is most pronounced at birth, obtaining fetal skin cells would be a prerequisite. However, as this procedure poses an unnecessary risk for mother and child, an alternative is needed. With the invention of induced pluripotent stem cells, any somatic cell can be transformed into a stem cell. This allows us to differentiate these stem cells to skin cells. In this study, the authors show that these cells have similar properties to actual fetal skin cells, as they express a marker of fetal, but not adult skin. Using this technique, we show that the degradation of keratin 14 is indeed higher in fetal-like compared to adult skin cells, in line with the clinical observation in patients. Further research is needed to unravel mechanisms related to ageing, that could explain these findings.

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