Journal Article

Loss of ceramide synthase 3 causes lethal skin barrier disruption

Richard Jennemann, Mariona Rabionet, Karin Gorgas, Sharon Epstein, Alexander Dalpke, Ulrike Rothermel, Aline Bayerle, Franciscus van der Hoeven, Silke Imgrund, Joachim Kirsch, Walter Nickel, Klaus Willecke, Howard Riezman, Hermann-Josef Gröne and Roger Sandhoff

in Human Molecular Genetics

Volume 21, issue 3, pages 586-608
Published in print February 2012 | ISSN: 0964-6906
Published online October 2011 | e-ISSN: 1460-2083 | DOI:
Loss of ceramide synthase 3 causes lethal skin barrier disruption

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The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1–6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (≥C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage.

Journal Article.  13265 words.  Illustrated.

Subjects: Genetics and Genomics

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