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Effect of depletion of PNPLA1 in gene expression during keratinocyte differentiation on reconstructed human epidermis

ABSTRACT: Congenital ichthyoses are rare and disabling genodermatoses caused by mutations in genes involved in the epidermal barrier. More than 60 genes are known to be involved. However, 5-10% of the genetic variants identified in those genes are rarely or not described and their pathogenicity not yet demonstrated. They are therefore classified as Variants of Uncertain Significance (VUS) that leave number of patients undiagnosed, precluding prognosis, counselling and treatment. We report here, an experimental strategy to reclassify VUS identified in congenital ichthyosis-causing genes tested for PNPLA1 variants. PNPLA is a transacylase essential for the skin barrier formation. It catalyzes the biosynthesis of acylceramides (AcylCer) in the stratum granulosum by esterification of ω-hydroxy ceramides with linoleic acid. We successfully characterized three PNPLA1 VUS identified in three patients with congenital ichthyosis, opening the possibility to extend the approach to other ichthyosis-causing genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272321 | GEO | 2025/12/04

REPOSITORIES: GEO

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Expression data from adult mouse epidermis upon tamoxifen induced inactivation of Alox12b

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.

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Expression data from newborn Alox12b knockout mouse epidermis

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Patients with Congenital Ichthyosis and TGM1 Mutations Overexpress Other ARCI Genes in the Skin: Part of a Barrier Repair Response?

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.

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