Burnlike scars: A sign suggestive of <scp>KLHL</scp>24‐related epidermolysis bullosa simplex

Alkhalifah, Azzam; Chiavérini, C.; Charlesworth, A.; Has, Cristina; Lacour, Jean‐Philippe

doi:10.1111/pde.13443

Cited by 14 publications

(13 citation statements)

References 5 publications

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“…Several cases with typical signs of EB and mutations in KLHL24 have been described since then. 21 , 22 , 23 , 24 , 25 It is estimated that 5% of cases of EB S are associated with mutations in this gene. 1 The typical clinical signs of this subtype of EB S are still being characterized, as more studies and more patients are being described.…”

Section: Epidermolysis Bullosa Simplexmentioning

confidence: 99%

Inherited epidermolysis bullosa: update on the clinical and genetic aspects

Mariath

Santin

Schüler‐Faccini

et al. 2020

Anais Brasileiros de Dermatologia

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Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.

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Section: Epidermolysis Bullosa Simplexmentioning

confidence: 99%

Inherited epidermolysis bullosa: update on the clinical and genetic aspects

Mariath

Santin

Schüler‐Faccini

et al. 2020

Anais Brasileiros de Dermatologia

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“…In contrast, the mutated protein KLHL24-ΔN28 is unable to undergo auto-ubiquitination and is consequently more stable. This results in excessive ubiquitination and therefore degradation of keratin 14, ultimately leading to skin fragility (4)(5)(6)(7).…”

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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“…We observed significantly reduced K14 expression the neonatal healthy-appearing skin of a KLHL24-mutated patient, and staining of skin at the age of 14 years showed normal K14 (Yenamandra et al, 2018), suggesting that KLHL24 regulation of K14 turnover may be more impaired during epidermal proliferation such as with body growth. The reported burnlike scars in patients with EBS due to KLHL24 mutations are not seen in EBS caused by mutations in other EBSassociated genes (Alkhalifa et al, 2018;He et al, 2016;Yenamandra et al, 2018). Additionally, Yenamandra et al reported an abnormal basement membrane structure with thickening and thinning of the lamina densa with re-duplications and blind offshoots typically encountered in poikiloderma, indicating other or additional skin pathology besides keratin filament fragility in basal keratinocytes in the case of perturbed KLHL24.…”

mentioning

confidence: 97%

“…In 2016, Lin et al (2016) and He et al (2016), using whole-exome sequencing, discovered dominant acting point mutations in the start codon of KLHL24 caused basal cell skin fragility. Since then, several other patients with basal EBS caused by KLHL24 mutations, all affecting the same start codon, have been reported (Alkhalifa et al, 2018;Lee et al, 2017;Yenamandra et al, 2018). KLHL24, unlike K5 and K14, is not a structural protein.…”

mentioning

confidence: 99%