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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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.

Original languageEnglish
Pages (from-to)2202-11
Number of pages10
JournalJournal of Investigative Dermatology
Volume133
Issue number9
DOIs
Publication statusPublished - Sep 2013
Externally publishedYes

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Ichthyosis
Ceramides
Chain length
Skin
Keratinocytes
Exfoliative Dermatitis
Exome
Lipids
Recombinant proteins
Acylation
Sphingolipids
Collodion
Missense Mutation
Mutant Proteins
Coenzyme A
Lipid Metabolism
Recombinant Proteins
Metabolism
Epidermis
Cornea

Cite this

Eckl, Katja-Martina ; Tidhar, Rotem ; Thiele, Holger ; Oji, Vinzenz ; Hausser, Ingrid ; Brodesser, Susanne ; Preil, Marie-Luise ; Onal-Akan, Aysel ; Stock, Friedrich ; Müller, Dietmar ; Becker, Kerstin ; Casper, Ramona ; Nürnberg, Gudrun ; Altmüller, Janine ; Nürnberg, Peter ; Traupe, Heiko ; Futerman, Anthony H ; Hennies, Hans C. / Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length. In: Journal of Investigative Dermatology. 2013 ; Vol. 133, No. 9. pp. 2202-11.
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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.",
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Eckl, K-M, Tidhar, R, Thiele, H, Oji, V, Hausser, I, Brodesser, S, Preil, M-L, Onal-Akan, A, Stock, F, Müller, D, Becker, K, Casper, R, Nürnberg, G, Altmüller, J, Nürnberg, P, Traupe, H, Futerman, AH & Hennies, HC 2013, 'Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length', Journal of Investigative Dermatology, vol. 133, no. 9, pp. 2202-11. https://doi.org/10.1038/jid.2013.153

Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length. / Eckl, Katja-Martina; Tidhar, Rotem; Thiele, Holger; Oji, Vinzenz; Hausser, Ingrid; Brodesser, Susanne; Preil, Marie-Luise; Onal-Akan, Aysel; Stock, Friedrich; Müller, Dietmar; Becker, Kerstin; Casper, Ramona; Nürnberg, Gudrun; Altmüller, Janine; Nürnberg, Peter; Traupe, Heiko; Futerman, Anthony H; Hennies, Hans C.

In: Journal of Investigative Dermatology, Vol. 133, No. 9, 09.2013, p. 2202-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length

AU - Eckl, Katja-Martina

AU - Tidhar, Rotem

AU - Thiele, Holger

AU - Oji, Vinzenz

AU - Hausser, Ingrid

AU - Brodesser, Susanne

AU - Preil, Marie-Luise

AU - Onal-Akan, Aysel

AU - Stock, Friedrich

AU - Müller, Dietmar

AU - Becker, Kerstin

AU - Casper, Ramona

AU - Nürnberg, Gudrun

AU - Altmüller, Janine

AU - Nürnberg, Peter

AU - Traupe, Heiko

AU - Futerman, Anthony H

AU - Hennies, Hans C

PY - 2013/9

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N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Ceramides

KW - Child

KW - Child, Preschool

KW - Disease Models, Animal

KW - Epidermis

KW - Exome

KW - Family Health

KW - Female

KW - Fibroblasts

KW - Genes, Recessive

KW - Homozygote

KW - Humans

KW - Ichthyosis, Lamellar

KW - Infant, Newborn

KW - Keratinocytes

KW - Male

KW - Mice

KW - Molecular Weight

KW - Mutation, Missense

KW - Pedigree

KW - Phenotype

KW - Sphingosine N-Acyltransferase

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

UR - http://www.sciencedirect.com/journal/journal-of-investigative-dermatology

U2 - 10.1038/jid.2013.153

DO - 10.1038/jid.2013.153

M3 - Article

VL - 133

SP - 2202

EP - 2211

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 9

ER -