ArticleThe Journal of clinical investigation2021
Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- [Overexpression of miR-183-5p enhances malignant phenotype and inhibits ferroptosis of triple-negative breast cancer cells by negatively regulating KLHL24].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- Xeno-Free Peptide-Functionalized Hydrogels Support hiPSC Encapsulation andbioRxiv : the preprint server for biology · 2026Article
- Structural-Molecular Linkage Shapes the Adaptive Traits of Nuptial Pads in Male Rana chensinensis.Cell biochemistry and function · 2026Article
- Biallelic KLHL24 Loss-of-Function Variants: Emerging Evidence for Early-Onset Arrhythmias and Hypertrophic Cardiomyopathy.JACC. Case reports · 2026Article
- KLHL24-Associated Hypertrophic Cardiomyopathy: When Genotype Outpaces Phenotype.JACC. Case reports · 2026Article
- Epidermolysis Bullosa Related to the KLHL24 Gene: A Rare Pediatric Manifestation of Arrhythmogenic Cardiomyopathy.JACC. Case reports · 2026Article
- Novel compound heterozygous mutations inFrontiers in cardiovascular medicine · 2026Article
- Long-Term Impact of Western Diet on Right Ventricular Transcriptome: Uncovering Sex-Specific Patterns in C57BL/6J Mice.International journal of molecular sciences · 2025Article
- Human Cardiac Organoids: Advances and Prospects from Construction to Preclinical Drug Evaluation.Cells · 2025Review
- A Micro-Engineered Heart Tissue Model of Desmin-related Cardiomyopathy Caused by Mutant αB Crystallin.bioRxiv : the preprint server for biology · 2025Article
- Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review.International journal of molecular sciences · 2024Review
- Retinoic acid modulation guides human-induced pluripotent stem cell differentiation towards left or right ventricle-like cardiomyocytes.Stem cell research & therapy · 2024Article
- EBS in Children with De Novo Pathogenic Variants DisturbingInternational journal of molecular sciences · 2024Article
- The new era of cardiovascular research: revolutionizing cardiovascular research with 3D models in a dish.Medical review (2021) · 2024Review
- Priorities in Cardio-Oncology Basic and Translational Science: GCOS 2023 Symposium Proceedings:JACC. CardioOncology · 2023Review
- FRESH™ 3D bioprinted cardiac tissue, a bioengineered platform forAPL bioengineering · 2023Article
- Retinal gliosis and phenotypic diversity of intermediate filament induction and remodeling upon acoustic blast overpressure (ABO) exposure to the rat eye.Experimental eye research · 2023Article
- Clinical Outcome inCirculation. Genomic and precision medicine · 2023Article
- A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation.The British journal of dermatology · 2022Article
- Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction.International journal of molecular sciences · 2022Review
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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