Keratin 14 Degradation and Aging in Epidermolysis Bullosa Simplex due to KLHL24 Gain-of-Function Variants

British Journal of Dermatology

Al-Shinnag

Silljé

et al. 2022

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Section: Figuresupporting

confidence: 83%

A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation

British Journal of Dermatology

Al-Shinnag

Silljé

et al. 2022

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“…This result was in line with a reduced expression and phenotype of the explanted heart of one of the patients [101]. Meanwhile, another study reported that KLHL24 is also responsible for the turnover of foetal-like keratins 7,8,17 and 18 [103], while degradation of keratin 14 may be higher in foetal-like hiPSC-derived keratinocytes compared to adult keratinocytes [102]. These data would explain why patients develop congenital aplasia cutis but only mild skin fragility later in life.…”

Section: Klhl24 Variants Causing An Altered Klhl24 Proteinsupporting

confidence: 52%

“…This seems to be a tight balance as the gain-of-function KLHL24 variants cause excessive breakdown of desmin and keratins. These results furthermore indicate that patients displaying variants that result in expression of Val2_Met29del would likely benefit from KLHL24 RNAi therapies, as this has effectively regained keratin and desmin protein levels in in vitro models [98,[100][101][102]. While unlikely to affect the skin, excessive RNAi can be detrimental to cardiac function, as absence of KLHL24 has been associated with HCM.…”

Section: Potential Therapeutic Avenuesmentioning

confidence: 82%

“…For instance, KLHL24 protein activity, whether through loss or gain of function, causes a strong dose-dependent phenotype in the heart, which seems directly related to expression of its target desmin [101,107]. The relationship to keratins in the skin is less straightforward and requires more cohesive data that may now be emerging with new studies [102][103][104]. Functional studies combined also suggest that the phenotype associated with DP reduction is both dose-and organ-dependent in nature, which is important knowledge for future interventions.…”

Section: Discussionmentioning

confidence: 99%

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Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

Andrei

Marsili

et al. 2022

IJMS

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Genetic variants in gene-encoding proteins involved in cell–cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype–phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype–phenotype correlations, we separate variants into ‘protein reducing’ or ‘altered protein’ variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation.

“…The differences between the in vivo skin situation and the in vitro characteristics of cultured keratinocytes from the same site may be caused by the extra demands on keratinocytes in culture and/or the lack of compensatory mechanisms present in the in vivo situation but lacking in in vitro culturing conditions. In that sense, three‐dimensional skin models, 32 derived from patient primary or hiPSC‐derived keratinocytes, 32‐34 could better mimic the situation of in vivo disease. Nonetheless, contrary to the seemingly normal DP protein intensity on IFM in both non‐palmoplantar skin and cultured keratinocytes of the same site, protein levels in cultured keratinocytes on blot showed significant DPI & II deficiency, reduction of desmocollin‐1 and desmocollin‐3, altered differentiation and impaired cell–cell contacts, without cell‐sheet dissociation after a KDA.…”

Section: Discussionmentioning

confidence: 99%

Functional investigation of two simultaneous or separately segregating DSP variants within a single family supports the theory of a dose‐dependent disease severity

Experimental Dermatology

Andrei

Kramer

et al. 2022

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Desmoplakin (DP) is an important component of desmosomes, essential in cell–cell connecting structures in stress‐bearing tissues. Over the years, many hundreds of pathogenic variants in DSP have been associated with different cutaneous and cardiac phenotypes or a combination, known as a cardiocutaneous syndrome. Of less than 5% of the reported DSP variants, the effect on the protein has been investigated. Here, we describe and have performed RNA, protein and tissue analysis in a large family where DSPc.273+5G>A/c.6687delA segregated with palmoplantar keratoderma (PPK), woolly hair and lethal cardiomyopathy, while DSPWT/c.6687delA segregated with PPK and milder cardiomyopathy. hiPSC‐derived cardiomyocytes and primary keratinocytes from carriers were obtained for analysis. Unlike the previously reported nonsense variants in the last exon of DSP that bypassed the nonsense‐mediated mRNA surveillance system leading to protein truncation, variant c.6687delA was shown to cause the loss of protein expression. Patients carrying both variants and having a considerably more severe phenotype were shown to have 70% DP protein reduction, while patients carrying only c.6687delA had 50% protein reduction and a milder phenotype. The analysis of RNA from patient cells did not show any splicing effect of the c.273+5G>A variant. However, a minigene splicing assay clearly showed alternative spliced transcripts originating from this variant. This study shows the importance of RNA and protein analyses to pinpoint the exact effect of DSP variants instead of solely relying on predictions. In addition, the particular pattern of inheritance, with simultaneous or separately segregating DSP variants within the same family, strongly supports the theory of a dose‐dependent disease severity.