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

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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 Önal-Akan, Friedrich Stock, Dietmar Müller, Kerstin Becker, Ramona Casper, Gudrun Nürnberg, Janine Altmüller, Peter Nürnberg, Heiko Traupe, Anthony H. Futerman, Hans C. Hennies Journal of Investigative Dermatology Volume 133, Issue 9, Pages 2202-2211 (September 2013) DOI: 10.1038/jid.2013.153 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Phenotype and pedigree. (a) Clinical characterization of patient VII:3 at the age of (i) 6 days, (ii and iii) 3 years, and (iv) 7 years. The girl was born as collodion baby and developed a moderate lamellar ichthyosis with pronounced keratotic lichenification with a prematurely aged appearance. (v) Hematoxylin and eosin (H&E) staining of skin sections demonstrated compact orthohyperkeratosis with mild acanthosis. (b) The pedigree contains multiple consanguinity. Question marks denote connections where the exact relationship is unknown. Individuals marked with a bar were clinically investigated by one of us. Subjects marked with + or # sign were included in the linkage analysis and samples from VI:4, VI:13, and VII:1 in the exome sequencing. Journal of Investigative Dermatology 2013 133, 2202-2211DOI: (10.1038/jid.2013.153) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Synthesis and activity of ceramide synthase 3 (CerS3). (a) Specific expression of CERS3 in the uppermost layer of the stratum granulosum and the transit zone to the stratum corneum in healthy skin as shown by immunohistochemistry with and without bright field depiction of the epidermis. (b–f) CerS3 and markers of epidermal differentiation in healthy (upper part) and patient skin (lower part). (b, c) Analysis of CerS3 with two different antibodies showed distinctive expression in the upper stratum granulosum in healthy skin in contrast to more diffuse expression in the granular and horny layers in the patient sample. Expression of (d) involucrin (IVL) was elevated and broader in patient skin. (e) Keratin 10 (K10) was unchanged in patient samples. Detection of (f) 12R-lipoxygenase (12R-LOX) was markedly broadened in the patient sample. Antibodies: green, 4',6-diamidino-2-phenylindole (DAPI): blue. Scale bars=25μm. (g–i) Ceramide synthase activity. (g) Intrinsic CerS3 was assayed using C26–coenzyme A (CoA) in homogenates from primary keratinocytes and lipids were separated by thin layer chromatography. N=3. (h) Western blot analysis confirmed expression of recombinant CerS3 in human embryonic kidney (HEK) cells and showed slightly reduced amounts of mutant CerS3 compared with wild type (arrow). The upper band seen here is supposed to represent an alternatively glycosylated form of CerS3 (Laviad et al., 2012; asterisk). (i) Overexpression of CerS3 indicated almost complete loss of enzyme activity caused by mutation p.Trp15Arg in vitro. NT, transfection control. Means±SD; N=3. Journal of Investigative Dermatology 2013 133, 2202-2211DOI: (10.1038/jid.2013.153) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Loss of very long acyl chain ceramides in patient keratinocytes. Free and protein-bound ceramides extracted from differentiated keratinocytes from patient and healthy controls were analyzed with liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). (a) Free nonhydroxylated ceramides, (b) free nonesterified hydroxylated ceramides, (c) free ω-hydroxylated ceramides esterified with linoleic acid, and (d) protein-bound ω-hydroxylated ceramides. Cer response ratio refers to the integrated peak area of the defined endogenous ceramide divided by the peak area of the internal standard. Means±SD; N=2 analytical replicates of N=4 biological replicates. Journal of Investigative Dermatology 2013 133, 2202-2211DOI: (10.1038/jid.2013.153) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Morphological characterization of patient skin and disease models. (a) Ultrastructural analysis of skin biopsy specimens of patients VII:1 and VII:3 showed mild acanthosis and moderate to strong orthohyperkeratosis. Cleft-like inclusions (C), possibly originating from unprocessed neutral lipids and partly containing melanosomal remnants, were frequently visible in horny lamellae, and irregular vesicular structures (V), partly with melanosomes, were present in the granular layer. Scale bars=2μm (i), 1μm (ii), 500nm (iii). (b) Reconstructed skin of patient VII:3 showed a compact, thickened stratum corneum with inhomogeneous lamellae and inconspicuous cornified cell envelopes. Lipid droplets (L) and vesicular inclusions (V) were frequently visible in the stratum corneum. Numbers of keratohyalin granules (k) and lamellar bodies (Lbs) were reduced and irregularly distributed in suprabasal layers. Scale bars=2.5μm (i and ii), 250nm (iii). (c–e) Reconstructed skin was characterized by antibodies against markers of epidermal differentiation. (c) Ceramide synthase 3 (CerS3) is present in upper granular and horny layers in normal models (upper part) and extended to earlier layers in disease models (lower part). (d) Loricrin (Lor) and (e) filaggrin (Flg) were present in layers of differentiated keratinocytes in controls (upper part) and also visible in earlier layers in disease models (lower part). Scale bar=25μm. (f, g) Reconstructed skin was used for dye penetration assays with Lucifer Yellow. Compared with (f) healthy skin, the permeability barrier function is reduced in (g) disease models as shown by visualization of Lucifer Yellow (left) and overlay with 4',6-diamidino-2-phenylindole (DAPI) staining (right). Scale bars=75μm (f), 25μm (g). Journal of Investigative Dermatology 2013 133, 2202-2211DOI: (10.1038/jid.2013.153) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions