128 Ichthyosis patients with TGM1 mutations show aberrant transcriptomic expression

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a group of rare genetic skin disorders affecting the cornification of epidermis. Etiologically, mutations in 9 genes have been demonstrated so far, with TGM1 being the most commonly affected gene. It encodes transglutaminase 1, which covalently bind w-hydroxy-ceramides to the corneocyte protein envelope to form cornified lipid envelop (CLE) that is crucial for skin lipid barrier function. Yet, the impact of TGM1 mutations on epidermal transcriptome remains elusive. Therefore, we performed oligoarray analysis with 4 healthy controls and 5 patients with TGM1 mutations, all of which were born as collodion babies. In total, 1221 transcripts were differentially expressed (Benjamini adjusted p<0.05) in the patients compared to controls. The differentially expressed genes were enriched in several important biological networks, such as epidermal keratinocyte differentiation, lipid processing oxidoreductase, CLE, and immunity. In particularly, the expressions of 8 other ichthyosis-causing genes (including syndromic forms) and some immune defensive genes, some of which have been validated by qPCR, were upregulated to variable extents. Moreover, some other genes encoding ceramide producing enzymes, such as GBA and SPTLC2, were also induced. This suggests that there are compensatory mechanisms elicited in TGm-1 deficient epidermis striving to restore the skin lipid barrier by producing more acylceramides and antimicrobial molecules.