title: Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.
abstract: 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.
authors.affiliation: Center for Dermatogenetics, University of Cologne, Cologne, Germany.
authors.forename: Katja-Martina
authors.initials: KM
authors.lastname: Eckl
authors.forename: Rotem
authors.initials: R
authors.lastname: Tidhar
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Oji
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Preil
authors.forename: Aysel
authors.initials: A
authors.lastname: Onal-Akan
authors.forename: Friedrich
authors.initials: F
authors.lastname: Stock
authors.forename: Dietmar
authors.initials: D
authors.lastname: Müller
authors.forename: Kerstin
authors.initials: K
authors.lastname: Becker
authors.forename: Ramona
authors.initials: R
authors.lastname: Casper
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Heiko
authors.initials: H
authors.lastname: Traupe
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hennies
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis* / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics* / Q000473:pathology*; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008970:Molecular Weight; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D051049:Sphingosine N-Acyltransferase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002518:Ceramides; C583317:CERS3 protein, human; D051049:Sphingosine N-Acyltransferase