Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures
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ABSTRACT:
PROVIDER: PRJNA793431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17395400.fastq.gz | Fastqsanger.gz | |||
| SRR17395401.fastq.gz | Fastqsanger.gz | |||
| SRR17395402.fastq.gz | Fastqsanger.gz | |||
| SRR17395403.fastq.gz | Fastqsanger.gz | |||
| SRR17395404.fastq.gz | Fastqsanger.gz |
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Project description:In this study we performed the first global RNA-seq analysis in 54 ichthyosis patients (7 Netherton syndrome/NS, 13 epidermolytic ichthyosis/EI, 16 lamellar ichthyosis/LI, 18 congenital ichthyosiform erythroderma/CIE) and 40 healthy controls. Differentially expressed genes (DEGs) were defined based on fold changes/FCH>2 and false discovery rate/FDR<0.05 criteria. We found robust and significant Th22/Th17 skewing in all subtypes (e.g. IL-17A/C/F, S100A7/8/9/12; p<0.001) with modest changes in Th2 pathway, primarily in NS, and Th1 skewing in CIE.
2022-03-06 | GSE192832 | GEO
Project description:The purpose of this study was to analyze the genomic signatures and profiles of skin from ichthyosis (various subtypes) vs. healthy patients. The analysis strategy was to study differentially expressed genes common to the ichthyosis shared phenotype, as well as individual ichthyosis subtypes, and compare and contrast to the genomic profiles of atopic dermatitis and psoriasis.
2018-10-10 | GSE108640 | GEO
Project description:Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding the development of targeted treatments. Thus, we sought to characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of patients with ichthyosis. We performed a global RNA-sequencing analysis in 54 patients with ichthyosis (7 with Netherton syndrome, 13 with epidermolytic ichthyosis, 16 with lamellar ichthyosis, and 18 with congenital ichthyosiform erythroderma) and 40 healthy controls. Differentially expressed genes were defined on the basis of fold changes > 2 and false discovery rate < 0.05 criteria. We found robust and significant T helper (Th) 22/Th17 skewing in all subtypes (e.g., IL-17A/C/F, S100A7/8/9/12; P < 0.001) with modest changes in Th2 pathway, primarily in Netherton syndrome, and Th1 skewing in congenital ichthyosiform erythroderma. Across all subtypes (less evident in epidermolytic ichthyosis), lipid metabolism and barrier junction markers were downregulated (e.g., FA2H, CDH10/11/12/2; P < 0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g., SPRR1A/1B/2C/2G, EREG; P < 0.05). Our findings suggest that the common ichthyosis variants share aberrations in Th17/Th22 and barrier function, with minimal Th2 modulation. This may help to elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.
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Project description:BackgroundThe ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking because the underlying molecular basis is poorly understood.ObjectiveWe sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics.MethodsWe analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT-PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI-E) and scaling (IASI-S); transepidermal water loss; and pruritus.ResultsIchthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T-cell and dendritic cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some TH1/interferon (IFN-γ) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF-α levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL-13 and IL-31) was similar to that seen in control subjects. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNF-α (IL-17A/C, IL-19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI-E scores strongly correlated with IL-17A (r = 0.74, P < .001) and IL-17/TNF-synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis.ConclusionOur data associate a shared TH17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL-17-targeting strategies.
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Project description:Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic skin disorders caused by mutations in any of >10 different genes, many of which are involved in epidermal synthesis of ω-O-acylceramides (acylCer), an essential precursor of the corneocyte lipid envelope that is also dependent on transglutaminase-1 for normal skin barrier formation. We hypothesized that inactivating TGM1 mutations, the most common cause of ARCI, might lead to a compensatory overexpression of transcripts involved in barrier repair, including 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 602 differentially expressed genes (adjusted P<0.05). Gene ontology analysis showed enrichment of mRNA encoding proteins associated with biological pathways mainly involved in keratinocyte differentiation and adaptive/innate immune response. Moreover, among non-syndromic ARCI-causing genes, seven out of twelve were significantly increased (log2fold -change=0.98-2.05). Four genes causing syndromic ichthyosis and seven other genes involved in biosynthesis of fatty acyl-CoA and ceramides were also significantly affected. This study reveals upregulation of several ichthyosis-causing genes in the skin of patients with TGM1 mutations, indicating a compensatory induction of acylCer biosynthesis as a part of a barrier repair mechanism.
2018-11-30 | GSE107462 | GEO
Project description:Skin microbiome ichthyosis
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Project description:SDR9C7 encodes an orphan short-chain dehydrogenase/reductase recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7 knockout model we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative LC-MS assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its non-enzymatic coupling to protein. This suggests a novel mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.
2019-11-07 | GSE135643 | GEO
Project description:Gene expression analysis of the epidermis from Lexicon Genetics Abca12 knockout mouse model of Harlequin Ichthyosis compared with wild type embryos to search for pathways specifically altered in the condition. Results indicate a large immune and inflammatory response occurs in the sterile environment of the uterus.
2014-09-16 | GSE56125 | GEO
Project description:Kallmann syndrome is a genetically heterogeneous condition and a treatable form of male infertility. Defects in KAL1 gene have been implicated in Kallmann syndrome, which can be associated with X-linked ichthyosis in contiguous gene syndromes. In order to uncover the genetic cause of two brothers with Kallmann syndrome and X-linked ichthyosis, a custom semiconductor targeted resequencing panel to detect seventeen Kallmann syndrome causal genes and STS gene was designed. Next-generation sequencing was performed using this panel in the two affected brothers and their normal parents. To validate the result, we applied CytoScan⢠HD array, quantitative real-time PCR and direct PCR electrophoresis analysis with the participants. The patients received clinical assessment, human chorionic gonadotropin treatment and follow-up for 39 months. The results showed that the two affected siblings have the same de novo deletion at Xp22.3 including exons 9-14 of KAL1 gene and entire STS gene but showed different phenotypes in some respects. The secondary sex characteristics of the patients were greatly improved after treatment. We firstly reported that a de novo homozygous deletion contribute to KS with bilateral cryptorchidism and unilateral renal agenesis or normal kidney development and developed a cost-effective and reliable semiconductor targeted resequencing panel for genetic diagnosis of Kallmann syndrome in routinely obtained samples. One of the two brothers with Kallmann syndrome and X-linked ichthyosis was analyzed for validation the results of the deletion detected by next-generation sequencing.
2015-12-05 | E-GEOD-58793 | biostudies-arrayexpress
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