Patients with Congenital Ichthyosis and TGM1 Mutations Overexpress Other ARCI Genes in the Skin: Part of a Barrier Repair Response?
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PROVIDER: PRJNA420190 | ENA |
REPOSITORIES: ENA
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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: Not available
| S-EPMC7379499 | biostudies-literature
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:Numerous genetic conditions give rise to a scaly skin phenotype as a result of impaired barrier function. Differences in appearance suggest the response of epidermal cells depends upon the basic defect. The present work characterizes the departure of afflicted corneocytes from normal as judged by their proteomic profiles in three types of autosomal recessive congenital ichthyosis arising from defects in the genes PNPLA1, SDR9C7 and TGM1. The results show that the profiles were distinctive, each displaying a set of altered protein levels, but with a subset of common alterations. Departure from the normal profile was examined at three different anatomic sites (forearm, forehead, leg). Reflecting that the normal protein profile differed at these sites, comparing profiles from afflicted subjects revealed that the alterations in profile were site-dependent. These results suggest proteomic profiling can provide a quantitative measure of departure from the normal state of epidermis. Further development may find application to diagnosis, including identification of new genetic defects, and may help understand signaling pathways perturbed by the basic defects, supplementing visual evaluation of treatment.
2018-08-17 | MSV000082828 | MassIVE
Project description:Ichthyosis molecular fingerprinting shows profound Th17-skewing and a unique barrier genomic signature
| PRJNA427924 | ENA
Project description:Autosomal recessive congenital ichthyosis (ARCI) is a group of rare inherited skin disorders characterized by remarkable hyperkeratosis. Transglutaminase 1 (TGM1) mutations have been reported to be involved in four different phenotypes of ARCI, including lamellar ichthyosis (LI), non-bullous congenital ichthyosiform erythroderma (NBCIE), bathing suit ichthyosis (BSI), and self-improving collodion ichthyosis (SICI) according to the clinical presentation and histopathology. TGM1 has been found as a defective gene in a large amount of patients with LI and some patients with NBCIE, BSI and SICI. To further understand the effect of TGM1 mutations in epidermal cells development, we performed the transcriptome analysis of HEK293T and HaCaT cells transfected with TGM1 shRNA, TGM1 wild-type and mutant clones. The transcriptomic analysis revealed the effects of TGM1 on cell-cell interaction by suppressing genes involved in the gap junctions, tight junctions and desmosomes. These findings suggested that the TGM1 deficiency disturbed the balance of keratinocytes proliferation and differentiation processes and impaired the epithelial barrier function. The results provided the basis for further understanding on the etiology of ARCI. To explore the functional impacts on some of the TGM1mutations identified, we cloned and transfected the TGM1 wild type and mutant clones into HEK293T and HaCaT cells. R142C and R348X sequence mutations observed in ARCI (Autosomal recessive congenital ichthyosis) patients were generated. The shRNA targeting TGM1 and a scrambled negative control were obtained from Invitrogen (Carlsbad, CA). The293T and HaCaT cells were transfected with over-expression clones carry either wild-type or mutated TGM1sequence. Cells were harvested 48 hours post-transfection.
2015-12-31 | E-GEOD-70859 | biostudies-arrayexpress
Project description:Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures
| PRJNA793431 | ENA
Project description:Mutations in PNPLA1 (patatin-like phospholipase domain containing 1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in highly differentiated keratinocytes, plays a crucial role in the biosynthesis of acylceramide, a lipid component essential for skin barrier function. Pnpla1-deficient mice showed neonatal lethality due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and impaired terminal differentiation of keratinocytes. In Pnpla1–/– epidermis, three unique linoleate-containing lipids, including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids, were almost absent with reciprocal increases in their precursors ω-hydroxy (glucosyl)ceramides and ω-hydroxy fatty acids, indicating that PNPLA1 catalyzes the ω-O-esterification step with linoleic acid to form acylceramides. Our results suggest that PNPLA1 represents the missing piece in the process of acylceramide biosynthesis required for establishment of a permeability barrier.
2016-12-23 | GSE87682 | GEO
Project description:Autosomal recessive congenital ichthyoses (ARCI) are a group of non-syndromic congenital keratinization disorders including harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma with a total prevalence of 1:200,000. Affected individuals who are often born as collodion babies present with generalized scaling of the skin. This reflects a physical compensation for the defective cutaneous permeability barrier underlying all ichthyoses. Inactivity of 12R-lipoxygenase (12R-LOX) is a frequent cause of ARCI. Epidermis-specific conditional knockout of Alox12b encoding 12R-LOX was established in mice using the Cre-Lox system. Tamoxifen-induced Alox12b inactivation in mouse skin caused an ichthyosis-like phenotype. We used microarray to compare the gene expression profile in the epidermis of mice after tamoxifen induced Alox12b inactivation with that of control animals. Inactivation of Alox12b was associated with the upregulation of genes involved in keratinization, cholesterol biosynthesis, and Fc-epsilon receptor signaling.
2019-03-01 | GSE127434 | GEO