Patients with congenital ichthyosis and TGM1 mutations overexpress other ARCI genes in the skin: Part of a barrier repair response?

Hanqian Zhang,Marie Virtanen,Anders Vahlquist,Hans Törmä,Maja Ericsson,Simone Weström

doi:10.1111/exd.13813

Hanqian Zhang, Marie Virtanen + Show 4 more

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https://doi.org/10.1111/exd.13813

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Journal: Experimental Dermatology	Publication Date: Dec 21, 2018
Citations: 12	License type: CC BY 4.0

Affiliation: Uppsala University

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a group of monogenic skin disorders caused by mutations in any of at least 12 different genes, many of which are involved in the epidermal synthesis of ω‐O‐acylceramides (acylCer). AcylCer are essential precursors of the corneocyte lipid envelope crosslinked by transglutaminase‐1 (TGm‐1), or a yet unidentified enzyme, for normal skin barrier formation. We hypothesized that inactivating TGM1 mutations will lead to a compensatory overexpression of the transcripts involved in skin barrier repair, including many other ARCI‐causing genes. Using microarray, we examined the global mRNA expression profile in skin biopsies from five ARCI patients with TGM1 mutations and four healthy controls. There were a total of 599 significantly differentially expressed genes (adjusted P < 0.05), out of which 272 showed more than 1.5 log2fold‐change (FC) up‐ or down‐regulation. Functional classification of the latter group of transcripts showed enrichment of mRNA encoding proteins mainly associated with biological pathways involved in keratinocyte differentiation and immune response. Moreover, the expression of seven out of twelve ARCI‐causing genes was significantly increased (FC = 0.98‐2.05). Also, many of the genes involved in keratinocyte differentiation (cornified envelope formation) and immune response (antimicrobial peptides and proinflammatory cytokines) were upregulated. The results from the microarray analysis were also verified for selected genes at the mRNA level by qPCR and at the protein level by semi‐quantitative immunofluorescence. The upregulation of these genes might reflect a compensatory induction of acylCer biosynthesis as a part of a global barrier repair response in the patient′s epidermis.

Highlights

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare monogenic skin disorders with a prevalence of1:100 000.[1]
ARCI is caused by mutations in any of the following known genes: TGM1, ALOXE3, ALOX12B, ABCA12, CYP4F22, CERS3, NIPAL4, PNPLA1, SDR9C7, LIPN, SLC27A4 and SULT2B1.[1,5,6,7] mutations in ELOVL4, GBA, GJB2, CLDN1, SPINK5, STS, FLG, KRT1, KRT10 and KRT2 can cause similar ichthyosis phenotypes.[1,8,9,10,11,12]
Among the first group of genes, the majority are involved in the biosynthesis of ω-O-acylceramides and one encodes for an enzyme transglutaminase-1 (TGm-1) which cross-links cornified envelope (CE) proteins and might be involved in forming the corneocyte lipid envelope (CLE).[1,13,14,15]

Summary

| INTRODUCTION

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare monogenic skin disorders with a prevalence of. Because TGm-1 is important in the final step of keratinization and many of the other mentioned gene products are preceding players in the formation of a skin barrier, a genetic deficiency of TGm-1 could hypothetically elicit compensatory gene regulations either via some pathway-specific feedback mechanisms or as a part of a more general epidermal repair mechanism. To address this possibility, which has barely been studied in the past, we examined the global mRNA profile and expression of specific proteins in epidermis of patients with TGM1 mutations compared with healthy controls

| MATERIALS AND METHODS

| Ethical statement

| DISCUSSION

| Study limitations

| CONCLUSION

CONFLICT OF INTEREST