Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length

Katja-Martina Eckl, Rotem Tidhar, Holger Thiele, Vinzenz Oji, Ingrid Hausser, Susanne Brodesser, Marie-Luise Preil, Aysel Onal-Akan, Friedrich Stock, Dietmar Müller, Kerstin Becker, Ramona Casper, Gudrun Nürnberg, Janine Altmüller, Peter Nürnberg, Heiko Traupe, Anthony H Futerman, Hans C Hennies

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The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.

Original languageEnglish
Pages (from-to)2202-11
Number of pages10
JournalJournal of Investigative Dermatology
Issue number9
Publication statusPublished - Sep 2013
Externally publishedYes


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