Modeling dilated cardiomyopathies in epidermolysis bullosa simplex patients using induced pluripotent stem cells with KLHL24 mutations (Raymond 1)Ongoing
|Dr Karine Raymond
|Leiden University Medical Center, Leiden, THE NETHERLANDS
|Start date / Duration
|01. Jul 2020 / 36 months
|Funder(s) / Co-Funder(s)
|DEBRA Austria, MSAP/EBEP Recommended
|EB genetics, epigenetics & biology
Publications related to the projectsGeneration and genetic repair of two human induced pluripotent cell lines from patients with Epidermolysis Bullosa simplex and dilated cardiomyopathy associated with a heterozygous mutation in the translation initiation codon of KLHL24 Characterization of the epidermal-dermal junction in hiPSC-derived skin organoids
Short lay summary
Mutations in KLHL24 genes cause a new form of epidermolysis bullosa simplex (EBS) associated with high risk of developing dilated cardiomyopathies (DCM). Clinical symptoms include denuded skin areas that heal quickly after birth, the presence of burn-like scars, skin atrophy, hair loss and nail defects. These patients also develop heart defects with ventricular dilation and impaired contraction that strongly affect their quality of life and are a potential source of mortality. The underlying mechanisms responsible for these heart anomalies are unknown and there is no treatment with proven efficacy to prevent these symptoms. Here, we wish to generate from skin tissue of patients with KLHL24 gene mutations, an in vitro human model of EBS-DCM by using the induced pluripotent stem cell (hiPSC) technology. By differentiating hiPSCs into heart cells, we will decipher in depth the heart phenotype and the mechanisms by which altered activity of KLHL24 contributes to the development of DCM.
Mutations in KLHL24 genes cause a new form of EBS associated with high risk of developing dilated cardiomyopathies (DCM). KLHL24 is a component of the ubiquitin-proteasome system that regulates protein turnover. Mutated KLHL24 proteins are more stable suggesting that excessive degradation of targeted substrates underlies disease development, although the mechanism is not resolved. Here, we aim to model DCM using hiPSCs harboring KLHL24 mutations and isogenic controls that will be differentiated into cardiomyocytes and supporting cells. By identifying KLHL24-substrates and by testing drugs, we expect to gain insights into KLHL24 functions in heart opening new avenues for treatments.
If validated, the hiPSC model of the combined EBS-DCM syndrome would be suitable for drug testing and could open new avenues for treatments in a group of patients that has no therapeutic option.