Identification of Novel Targetable Signaling Pathways in the Inherited Ichthyoses
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In this study the non-syndromic ichthyoses were studied to evaluate any genes or biological processes common to them and to identify key genes and pathways pertaining to each ichthyosis individually. This group of monogenic diseases comprises of ichthyosis vulgaris (loss of FLG), X-linked ichthyosis (loss of STS) lamellar ichthyosis/congenital ichthyosiform erythroderma (due to mutations in ALOX12B, ICH, ABCA12) and harlequin ichthyosis (due to ABCA12). They all affect terminal differentiation and the cornified layer and manifest as scaly conditions along a spectrum ranging from mild (as in ichthyosis vulgaris) to having a major impact on quality of life (as in lamellar ichthyosis/congenital ichthyosiform erythroderma) to severe (as in harlequin ichthyosis). The aim of this study was to investigate the effect of ichthyosis gene knockdown (STS, FLG, ABCA12, TGM1, ICH and ALOX12B) using RNAi technology in primary neonatal keratinocytes. 3D in vitro cultures using primary keratinocytes for the ichthyosis of interest, from the same genetic background, were developed including a novel model (STS knockdown). All the ichthyosis gene knockdowns in this study affected terminal differentiation (change in TGM1 expression) and loss of ABCA12 altered early differentiation in addition to terminal differentiation. RNA-Seq analysis was performed in primary keratinocytes transfected with siRNA. 62 genes were significantly down-regulated and 26 genes were significantly up regulated overlapping in all the ichthyoses models. Altered gene clusters were found for cell cycle, innate immune response, keratin filament/cytoskeleton and metabolism of lipids and lipoproteins. Functional studies showed an altered cytokine profile in unstimulated primary keratinocytes and following stimulation of TLR -2, -3, -5 in all the ichthyoses. The findings suggest that several overlapping genes involved in biological processes, including innate immunity, are altered in this group of non-syndromic, monogenic ichthyoses.
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