Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation–associated cardiomyopathy

Grilletta, Erica Ann

doi:10.1016/j.jdcr.2019.08.009

Cited by 11 publications

(10 citation statements)

References 7 publications

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“…We recently were the first to report a link between the heterozygous gain of function KLHL24:c.1A>G mutation (Met1Val) causing epidermolysis bullosa simplex (EBS) in skin and dilated cardiomyopathy (DCM) of the heart (1). Following our initial observation, around 33 patients with similar gain of function mutations leading to DCM have been reported (2,3). Despite these publications, the causative effects of gain of function mutations in KLHL24 leading to cardiomyopathy have not yet been established.…”

Section: Introductionmentioning

confidence: 99%

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

Vermeer¹,

Bolling²,

Bliley³

et al. 2021

Journal of Clinical Investigation

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The start codon c.1A>G mutation in KLHL24, encoding ubiquitin-ligase KLHL24, results in the loss of 28 Nterminal 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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Section: Introductionmentioning

confidence: 99%

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

Vermeer¹,

Bolling²,

Bliley³

et al. 2021

Journal of Clinical Investigation

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“…Ibernon-Moya et al presented a 6-year-old child with RDEB admitted to ICU due to cardiomegaly, pulmonary oedema, decreased EF and cardiogenic shock with a progressive worsening of the clinical status and death despite appropriate intensive treatment [ 8 ]. Grilletta described a case of a 14-year-old girl with EBS-KLHL24 with DC and symptoms of HF, with EF 19%, who required implantation of a LV assist and then underwent heart transplantation [ 15 ]. A 14-year-old boy with RDEB and EF 12% who did not respond to HF treatment and died within 1 month was reported by Shipman et al [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Some authors advocate a routine screening for DC including TTE, electrocardiograms and biomarkers of HF such as the brain natriuretic peptide level in EB patients [ 12 , 15 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…There is no established algorithm for performing cardiac evaluation in patients with EB because the majority of patients did not reveal any signs of heart disease. Some authors advocate a routine screening for DC including TTE, electrocardiograms and biomarkers of HF such as the brain natriuretic peptide level in EB patients [12,15,27]. Interestingly, Auckburally et al tried to determine the frequency of TTE screening in patients with severe types of EB.…”

Section: A -Maximal Velocity Of the Atrial Wave A Rev -Pulmonary Venous Atrial Reversal Velocity D -Pulmonary Venous Flow Diastolic Velocmentioning

confidence: 99%

“…Cases of dilated cardiomyopathy (DC), defined as a significant left ventricle (LV) systolic dysfunction and its enlargement, were most frequently reported [10][11][12]. This serious complication was predominantly observed in recessive DEB (RDEB) and also in JEB and EBS [12][13][14][15]. Transthoracic echocardiography (TTE) was usually a diagnostic tool used to detect heart disease.…”

Section: Introductionmentioning

confidence: 99%

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The analysis of echocardiographic results in patients suffering from epidermolysis bullosa

Kurnicka

Osipowicz

Dzikowska-Diduch

et al. 2020

pdia

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Introduction Cardiac abnormalities revealed in patients suffering from epidermolysis bullosa (EB) include dilated cardiomyopathy (DC) and aortopathy. DC is a rare but serious complication associated with an increased mortality, predominantly observed in recessive dystrophic EB. Echocardiography is the most available diagnostic tool used to detect heart disease in EB patients. Aim To analyse echocardiographic results obtained in Polish EB patients and compare them between the EB group and healthy persons. Material and methods We analysed retrospectively echocardiograms of 23 patients with EB (14 F, mean age 17.3 years) performed from 2017 to 2019. The incidence of left ventricular (LV) systolic and diastolic dysfunction, right heart disease and congenital heart disease was evaluated. A comparison of echo-parameters between EB patients and 20 matched healthy subjects was performed. Results We did not find any cases of DC and aortopathy in the EB group. One bicuspid aortic valve case was revealed. Analysis of LV diastolic parameters showed that the mean value of mitral A velocity was significantly higher and the pulmonary venous flow D velocity was lower in the EB group than in controls. Tissue Doppler analysis revealed lower values of E’ velocities of mitral annulus in the EB group, what may suggest discreetly slower LV relaxation, however, this will definitely require further research. Conclusions Although most EB patients do not present cardiac symptoms, there is still a risk of developing cardiomyopathy associated with poor prognosis. It seems reasonable to perform a scheduled echocardiographic screening including LV systolic and diastolic function assessment to detect preclinical cardiac abnormalities.

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Epidermolysis Bullosa

Has,

Bruckner-Tuderman,

Uitto

2025

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics

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Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation–associated cardiomyopathy

Cited by 11 publications

References 7 publications

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

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

The analysis of echocardiographic results in patients suffering from epidermolysis bullosa

Epidermolysis Bullosa

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