| Autor: |
Vermeer MC; Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands., Bolling MC; Department of Dermatology, University Medical Center Groningen, Groningen, Netherlands., Bliley JM; Department of Biomedical Engineering, Department of Materials Science & Eng, Carnegie Mellon University, Pittsburgh, United States of America., Arevalo Gomez KF; Department of Cardiology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, Netherlands., Pavez-Giani MG; Department of Cardiology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, Netherlands., Kramer D; Department of Dermatology, University Medical Center Groningen, Groningen, Netherlands., Romero-Herrera PH; Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands., Westenbrink BD; Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands., Diercks GF; Department of Pathology, University Medical Center Groningen, Groningen, Netherlands., van den Berg MP; Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands., Feinberg AW; Department of Biomedical Engineering, Department of Materials Science & Eng, Carnegie Mellon University, Pittsburgh, United States of America., Silljé HHW; Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands., van der Meer P; Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands. |
| Abstrakt: |
The start codon c.1A>G mutation in KLHL24, encoding ubiquitin-ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon. In skin, KLHL24-ΔN28 leads to gain of function, excessively targeting intermediate filament keratin-14 for proteasomal degradation, ultimately causing epidermolysis bullosa simplex (EBS). The majority of these EBS-patients are also diagnosed with dilated cardiomyopathy (DCM), but the pathological mechanism in the heart is unknown. As desmin is the cardiac homologue of keratin-14, we hypothesized that KLHL24-ΔN28 leads to excessive degradation of desmin, resulting in DCM. Dynamically loaded engineered heart tissues (dyn-EHTs) were generated from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from two patients and three (non)familial controls. Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients' explanted heart. This was accompanied by tissue dilatation, impaired mitochondrial function, decreased force values and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation. KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. To conclude, presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function, that can be prevented by restoring desmin protein levels. |
