Publication: Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues

De study of Mathilde Vermeer et al., published ahead of print in Journal of Clinical Investigation, shows that genetic mutations that lead to a hyperactive KLHL24 protein, cause degradation of desmin in the heart, leading to dilated cardiomyopathy in patients. This study is a result of a collaboration between the department of cardiology (Herman Silljé and principle investigator Peter van der Meer) and dermatology (Marieke Bolling). It is furthermore part of an ongoing Trans-Atlantic collaboration with Adam W. Feinberg of Carnegie Mellon University in Pittsburgh.


Inherited cardiomyopathy in combination with blistering disease

Inherited cardiomyopathies are prevalent diseases with many cases of unknown etiology. 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. During adulthood, many of these patients have additionally been diagnosed with dilated cardiomyopathy, however, the mechanism in the heart remained unknown. Currently, it is impossible to investigate cardiac myocytes, derived from hearts of living patients. However, 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 cardiac myocytes, in order to investigate patient-specific heart cells in an indirect way. Using this technique, we show that KLHL24 is involved in the turnover of desmin. Desmin is an important protein in heart and skeletal muscle that functions as a compliance network to prevent (heart) muscle deformations, like keratin 14 acts as part of a compliance network to prevent skin deformations. Absence of desmin or desmin aggregates are toxic for the cell, causing loss of tissue compliance. This results in thinning and weakening of heart muscle which ultimately causes loss of contractility.


Most important findings

Because desmin functions as a compliance network to prevent tissue deformations, we made use of a bendable strip that applies pressure to human engineered heart tissues. In health, this so-called dynamic loading improves the contractile power, with tissues displaying uniform contractile properties. However, in tissues derived from patients with a genetic mutation in the gene KLHL24, resulting in hyperactivity of KLHL24 protein, dynamic loading resulted in thin, dilated tissues with non-uniform contractile properties. Desmin was significantly reduced in diseased tissues, which corresponded with reduced desmin levels in the explanted heart of one of the patients. Reduction of KLHL24 expression or direct desmin overexpression was able to regain desmin protein levels in diseased engineered heart tissues, which prevented the phenotype.

In conclusion, we show that patients with hyperactivity of KLHL24, have a deficiency of desmin causing dilated cardiomyopathy, which can potentially be prevented by reducing KLHL24 gene expression in the heart.