The Proteolytic Network in Palmoplantar Keratoderma: SERPINA12 Joins the Family

Steele, Lloyd; Tawfik, Soha S; O’Toole, Edel A.

doi:10.1016/j.jid.2020.06.031

Cited by 3 publications

(2 citation statements)

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“…were the first to identify biallelic loss‐of‐function variants in SERPINA12 , which encodes a visceral adipose tissue‐derived serine protease inhibitor, as the underlying cause of the autosomal recessive nonmutilating diffuse PPK 6 . This type of PPK shares similar clinical features with other PPKs caused by protease overactivity, including skin peeling, erythema, hyperkeratotic palms and soles, and a whitish spongy change after water exposure 7 . Since the report by Mohamad et al ., no additional cases of SERPINA12 ‐related PPK have been reported.…”

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confidence: 99%

“…6 This type of PPK shares similar clinical features with other PPKs caused by protease overactivity, including skin peeling, erythema, hyperkeratotic palms and soles, and a whitish spongy change after water exposure. 7 Since the report by Mohamad et al, no additional cases of SERPINA12-related PPK have been reported. Here we present six new cases of PPK caused by novel SERPINA12 variants.…”

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Novel and founder variants of SERPINA12 in Chinese patients with autosomal recessive palmoplantar keratoderma

et al. 2022

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cells among half of the cohort, which would be expected for a common unifying origin.Differential gene expression analysis revealed T cells with shared TCRs to be enriched for central memory markers, including CD69, SELL (CD62L) and the Th2-skewing transcription factor JunB (Figure 1b). By contrast, T cells with unique TCRs were more Th1 polarized, as reflected by their expression of STAT1, CX3CR1, GNLY, LGALS1, S100A9 and S100A10. Module scores using well-defined gene sets for Th1, Th2 and central memory phenotypes supported this transcriptional dichotomy (Figure 1c). In addition, protein expression measured by AbSeq revealed that shared TCRs were chronically antigen experienced with an amplified expression of LAG3 and TIM3, 5 which are enriched among cutaneous neoplastic T cells and promote tumorigenesis (Figure 1d). These findings collectively demonstrate that TCR usage phenotypically segregates S ezary cells based on distinct origins in their pathogenesis.Immune dysregulation induced by staphylococcal toxins has been reported to drive the Th2 cytokine production that is characteristic of SS. 2,4 We found that this phenotype was reproduced among S ezary cells with a shared toxinresponsive TCR, supporting the hypothesis that infectious agents influence this neoplastic process. On the other hand, these findings may also reflect inherent VDJ recombination biases that occur during thymocyte development, as TRBV20-1*01 and other staphylococcal toxin-responsive TCRs have been reported to be preferentially utilized by T cells among healthy individuals as well as patients with CTCL. 6 The presence of a Th2 profile among malignant cells could represent one carcinogenic pathway whereby the nuclear accumulation of the NLRP3 inflammasome promotes a positive Th2 feedback loop that bolsters cellular proliferation and resistance to apoptosis. 7 Interestingly, antibodymediated blockade of programmed death-1 enriched among S ezary cells blunts Th2 cytokine production but reciprocally and paradoxically unleashes their proliferation potential, 8 suggesting the Th2 cytokine profile may be a by-product rather than a primary instigator of disease progression.The high frequency of the Th2 cytokine profile observed among patients with SS may reflect the ubiquitous nature by which S. aureus is recovered from patients with CTCL. CTCL affects an older population with a naturally impaired skin barrier that fosters S. aureus overgrowth. Nevertheless, other factors also contribute to the pathogenesis of CTCL, as S. aureus is only identified in a subset of patients, and the contextual role of S. aureus as a natural commensal or pathogenic strain is difficult to dissociate. If S. aureus promotes the classic Th2 phenotype, these findings may help identify patients who respond to targeted Th2 depletion with the anti-CCR4 therapy mogamulizumab. Future studies aimed at unravelling the role of S. aureus in instigating CTCL may be pivotal for developing targeted therapies.

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Novel and founder variants of SERPINA12 in Chinese patients with autosomal recessive palmoplantar keratoderma

et al. 2022

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Proteolytic and Antiproteolytic Activity in the Skin: Gluing the Pieces Together

Peled,

Sprecher

2024

Journal of Investigative Dermatology

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Defective cathepsin Z affects EGFR expression and causes autosomal dominant palmoplantar keratoderma

Malovitski

Sarig²,

Feller

et al. 2023

British Journal of Dermatology

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Background Abnormal function of the epidermal growth factor receptor (EGFR) has been recently shown to underlie various disorders of cornification. Objectives Here we aimed at delineating the genetic basis of a novel dominant form of palmoplantar keratoderma (PPK). Methods We used whole exome and direct sequencing, RT-qPCR, protein modelling, confocal immunofluorescence microscopy, immunoblotting, three-dimensional skin equivalents and an enzyme activity assays. Results Whole exome sequencing revealed heterozygous variants (c.274T > C and c.305C > T) in CTSZ encoding cathepsin Z in four individuals with focal PPK, who belong to three unrelated families. Bioinformatics and protein modeling predicted the variants to be pathogenic. Previous studies suggested that EGFR expression may be subject to cathepsin regulation. Immunofluorescence staining revealed reduced cathepsin Z expression in the upper epidermal layers and concomitant increased epidermal EGFR expression in patients harboring CTSZ variants. Accordingly, human keratinocytes transfected with constructs expressing PPK-causing variants in CTSZ displayed reduced cathepsin Z enzymatic activity as well as increased EGFR expression. In line with the role played by EGFR in the regulation of keratinocyte proliferation, human keratinocytes transfected with the PPK-causing variants, showed significantly increased proliferation which was abolished upon exposure to erlotinib, an EGFR inhibitor. Similarly, downregulation of CTSZ resulted in increased EGFR expression and increased proliferation in human keratinocytes, suggestive of a loss-of-function effect of the pathogenic variants. Finally, 3-dimensional organotypic skin equivalents grown from CTSZ-downregulated cells showed increased epidermal thickness and EGFR expression as seen in patient skin; here too, erlotinib was found to rescue the abnormal phenotype. Conclusions Taken collectively, these observations attribute to cathepsin Z a hitherto unrecognized function in epidermal differentiation.

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The Proteolytic Network in Palmoplantar Keratoderma: SERPINA12 Joins the Family

Cited by 3 publications

References 11 publications

Novel and founder variants of SERPINA12 in Chinese patients with autosomal recessive palmoplantar keratoderma

Novel and founder variants of SERPINA12 in Chinese patients with autosomal recessive palmoplantar keratoderma

Proteolytic and Antiproteolytic Activity in the Skin: Gluing the Pieces Together

Defective cathepsin Z affects EGFR expression and causes autosomal dominant palmoplantar keratoderma

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