Role of lipids in the formation and maintenance of the cutaneous permeability barrier.

Ceramide synthesis in the epidermis

Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology.

Metabolism of very long-chain Fatty acids: genes and pathophysiology.

Ceramide synthases as potential targets for therapeutic intervention in human diseases

To understand the regulation of tissue-specific gene expression, the GTEx Consortium generated RNA-seq expression data for more than thirty distinct human tissues. This data provides an opportunity for deriving shared and tissue specific gene regulatory networks on the basis of co-expression between genes. However, a small number of samples are available for a majority of the tissues, and therefore statistical inference of networks in this setting is highly underpowered. To address this problem, we infer tissue-specific gene co-expression networks for 35 tissues in the GTEx dataset using a novel algorithm, GNAT, that uses a hierarchy of tissues to share data between related tissues. We show that this transfer learning approach increases the accuracy with which networks are learned. Analysis of these networks reveals that tissue-specific transcription factors are hubs that preferentially connect to genes with tissue specific functions. Additionally, we observe that genes with tissue-specific functions lie at the peripheries of our networks. We identify numerous modules enriched for Gene Ontology functions, and show that modules conserved across tissues are especially likely to have functions common to all tissues, while modules that are upregulated in a particular tissue are often instrumental to tissue-specific function. Finally, we provide a web tool, available at mostafavilab.stat.ubc.ca/GNAT, which allows exploration of gene function and regulation in a tissue-specific manner.

/pdf/sharing-and-specificity-of-co-expression-networks-across-35-2qkd1g3dp1.pdf

Sharing and Specificity of Co-expression Networks across 35 Human Tissues.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q263 Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289) Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis

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Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.

The following information was missing from the Funding section: "This work has been supported in part by grants to M. Lathrop from Genome Quebec, le Ministere de l'Enseignement superieur, de la Recherche, de la Science et de la Technologie (MESRST) Quebec, and from the ANR in France for the Labex project "Medical Genomics".

Correction: Mutations in CERS3 Cause Autosomal Recessive Congenital Ichthyosis in Humans.

Resume Introduction Le pseudoxanthome elastique (PXE) est une affection hereditaire caracterisee par une atteinte cutanee, oculaire et cardiovasculaire. Nous avons analyse les atteintes oculaires des cas de PXE observes dans notre hopital. Methodes Onze patients atteints de PXE ont eu un examen ophtalmologique a la recherche de manifestations oculaires. Resultats Tous les patients avaient des manifestations oculaires. Il s’agissait de stries angioides chez 7 patients (63%). Quatre patients avaient un aspect en peau d’orange du fond d’œil. Deux patients avaient une atteinte maculaire et un patient avait des drusen du nerf optique. Conclusion L’examen ophtalmologique doit etre systematique et regulier pour mettre en evidence ces manifestations et diagnostiquer les complications rapidement.

Bourane Kamoun

Papers

Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.

Correction: Mutations in CERS3 Cause Autosomal Recessive Congenital Ichthyosis in Humans.

Atteinte oculaire au cours du pseudoxanthome élastique