Summary Background Pemphigus vulgaris (PV) is a life‐threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody‐mediated abnormal epidermal cell–cell adhesion and secretion of proinflammatory mediators by keratinocytes. Objectives To delineate the mechanism through which ST18 contributes to destabilization of cell–cell adhesion. Methods We used quantitative reverse‐transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site‐directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. Results The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell–cell adhesion in a tumour necrosis factor (TNF)‐α‐dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF‐α in the skin of patients with PV carrying an ST18‐associated PV risk variant, which was found to be associated with a more extensive PV phenotype. Conclusions Our findings suggest a role for TNF‐α in mediating the deleterious effect of increased ST18 expression in PV skin.

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Ribosome biogenesis is a highly energy-demanding process in eukaryotes which requires the concerted action of all three RNA polymerases. In RNA polymerase II transcription, the general transcription factor TFIIH is recruited by TFIIE to the initiation site of protein-coding genes. Distinct mutations in TFIIH or TFIIE lead to the rare autosomal recessive disorder trichothiodystrophy (TTD) characterized by a variety of symptoms including brittle hair, ichthyosis, and premature aging symptoms. While TFIIH is known to play an additional role in the production of ribosomal RNA (rRNA) by RNA polymerase I, the involvement of TFIIE in the RNA polymerase I transcription remains unknown. Here we uncovered an unexpected role of TFIIE in rRNA synthesis by RNA polymerase I. With high resolution microscopy we detected TFIIE in the nucleolus, at the site of active rRNA production. With specific inhibition of the RNA polymerase I transcription, TFIIE de-localizes from the nucleolus, implying RNA polymerase I transcription-dependent localization of TFIIE to the nucleolus. Mutations in TFIIE affects gene-occupancy of RNA polymerase I, rRNA maturation, ribosomal assembly and performance. In consequence, the elevated translational error rate with imbalanced protein synthesis and turnover results in an increase in heat-sensitive proteins. The results of our study unravel a novel role of TFIIE in RNA polymerase I transcription and identify loss of proteostasis as a possible pathomechanism in TTD.

Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotypephenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no | 1291 MOHAMAD et Al.

Autosomal recessive congenital ichthyosis (ARCI) refers to a large and genetically heterogenous group of non‐syndromic disorders of cornification featuring diffuse scaling. Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome is a rare autosomal recessive syndromic form of ichthyosis. The disease usually results from premature termination codon‐causing pathogenic variants in CLDN1 encoding CLAUDIN‐1 (CLDN1). We used whole exome sequencing (WES), Sanger sequencing, 3D protein modeling, Western blotting, and immunofluorescence confocal microscopy to delineate the genetic basis of ichthyosis in two siblings with ichthyosis but no other ectodermal abnormalities. One of the two siblings underwent liver transplantation in early childhood due to biliary atresia. Both patients were found to carry a homozygous missense pathogenic variant, c.242G>A (p.Arg81His), in CLDN1. The variant resulted in decreased CLDN1 expression in patient skin. 3D protein modeling predicted that p.Arg81His induces deleterious conformational changes. Accordingly, HaCaT cells transfected with a construct expressing the mutant CLDN1 cDNA featured decreased levels and mislocation of CLDN1 as compared with cells expressing the wildtype cDNA. In conclusion, we describe the first pathogenic missense variant in CLDN1 shown to result in ARCI.

Background The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. Objectives To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. Methods We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. Results Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HSassociated clinical features (25Á9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). Conclusions The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS.What is already known about this topic?• The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. • However, the pathomechanism underlying this association and its true prevalence are unknown.What does this study add?• A dual phenotype consisting of PC and HS was found to be associated with a pathogenic variant in KRT17. • This variant was found to affect NOTCH signalling, which has been previously implicated in HS pathogenesis.

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