{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:16:44Z","timestamp":1792066604326,"version":"4.4.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,10,23]],"date-time":"2021-10-23T00:00:00Z","timestamp":1634947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["CRC\/TR-156"],"award-info":[{"award-number":["CRC\/TR-156"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["19-09135\u00a0J"],"award-info":[{"award-number":["19-09135\u00a0J"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Functional skin barrier requires sphingolipid homeostasis; 3-ketodihydrosphingosine reductase or KDSR is a key enzyme of sphingolipid anabolism catalyzing the reduction of 3-ketodihydrosphingosine to sphinganine. Biallelic mutations in the KDSR gene may cause erythrokeratoderma variabilis et progressive-4, later specified as PERIOPTER syndrome, emphasizing a characteristic periorifical and ptychotropic erythrokeratoderma. We report another patient with compound heterozygous mutations in KDSR, born with generalized harlequin ichthyosis, which progressed into palmoplantar keratoderma. To determine whether patient-associated KDSR mutations lead to KDSR substrate accumulation and\/or unrecognized sphingolipid downstream products in stratum corneum (SC), we analyzed lipids of this and previously published patients with non-identical biallelic mutations in KDSR. In SC of both patients, we identified \u2018hitherto\u2019 unobserved skin ceramides with an unusual keto-type sphingoid base in lesional and non-lesional areas, which accounted for up to 10% of the measured ceramide species. Furthermore, an overall shorter mean chain length of free and bound sphingoid bases was observed\u2014shorter mean chain length of free sphingoid bases was also observed in lesional psoriasis vulgaris SC, but not generally in lesional atopic dermatitis SC. Formation of keto-type ceramides is probably due to a bottle neck in metabolic flux through KDSR and a bypass by ceramide synthases, which highlights the importance of tight intermediate regulation during sphingolipid anabolism and reveals substrate deprivation as potential therapy.<\/jats:p>","DOI":"10.1093\/hmg\/ddab309","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T19:09:52Z","timestamp":1634843392000},"page":"1105-1114","source":"Crossref","is-referenced-by-count":18,"title":["Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients"],"prefix":"10.1093","volume":"31","author":[{"given":"Robert","family":"Pilz","sequence":"first","affiliation":[{"name":"Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luk\u00e1\u0161","family":"Op\u00e1lka","sequence":"additional","affiliation":[{"name":"Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Skin Barrier Research Group, Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Majcher","sequence":"additional","affiliation":[{"name":"Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Skin Barrier Research Group, Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Grimm","sequence":"additional","affiliation":[{"name":"Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel","family":"Van Maldergem","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique Humaine, Universit\u00e9 de Franche-Comt\u00e9, 25000 Besan\u00e7on, France"},{"name":"Clinical Investigation Center 1431, National Institute of Health and Medical Research (INSERM), University Hospital, 25000 Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Mihalceanu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty of the University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Knut","family":"Sch\u00e4kel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty of the University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Enk","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty of the University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Aubin","sequence":"additional","affiliation":[{"name":"Service de Dermatologie et INSERM 1098 RIGHT, CHU et UFR Sant\u00e9, 25000 Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Claire","family":"Bursztejn","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Nancy, 54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Brischoux-Boucher","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique Humaine, Universit\u00e9 de Franche-Comt\u00e9, 25000 Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-9458","authenticated-orcid":false,"given":"Roger","family":"Sandhoff","sequence":"additional","affiliation":[{"name":"Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,23]]},"reference":[{"key":"2022040211410523600_ref1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1194\/jlr.S091827","article-title":"A perilous path: the inborn errors of sphingolipid metabolism","volume":"60","author":"Dunn","year":"2019","journal-title":"J. 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Genet."},{"key":"2022040211410523600_ref20","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1016\/j.jid.2017.06.028","article-title":"Biallelic mutations in KDSR disrupt ceramide synthesis and result in a spectrum of keratinization disorders associated with thrombocytopenia","volume":"137","author":"Takeichi","year":"2017","journal-title":"J. Invest. Dermatol."},{"key":"2022040211410523600_ref21","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1111\/jdv.15089","article-title":"The PERIOPTER syndrome (periorificial and ptychotropic erythrokeratoderma): a new Mendelian disorder of cornification","volume":"33","author":"Bursztejn","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"2022040211410523600_ref22","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.3324\/haematol.2018.204784","article-title":"Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia","volume":"104","author":"Bariana","year":"2019","journal-title":"Haematologica"},{"key":"2022040211410523600_ref23","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/j.jid.2019.11.029","article-title":"Palmoplantar keratoderma with leukokeratosis anogenitalis caused by KDSR mutations","volume":"140","author":"Huber","year":"2020","journal-title":"J. Invest. Dermatol."},{"key":"2022040211410523600_ref24","doi-asserted-by":"crossref","first-page":"278","DOI":"10.24920\/003656","article-title":"A homozygotic mutation in KDSR may cause keratinization disorders and thrombocytopenia: a case report","volume":"35","author":"Liu","year":"2020","journal-title":"Chin. Med. Sci. J."},{"key":"2022040211410523600_ref25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jdcr.2021.06.006","article-title":"Progressive symmetrical erythrokeratoderma manifesting as harlequin-like ichthyosis with severe thrombocytopenia secondary to a homozygous 3-ketodihydrosphingosine reductase mutation","volume":"14","author":"Altawil","year":"2021","journal-title":"JAAD Case Rep."},{"key":"2022040211410523600_ref26","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S0021-9258(18)63398-8","article-title":"Specificity in ceramide biosynthesis from long chain bases and various fatty acyl coenzyme A's by brain microsomes","volume":"245","author":"Morell","year":"1970","journal-title":"J. Biol. Chem."},{"key":"2022040211410523600_ref27","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/j.1471-4159.1978.tb06540.x","article-title":"In vivo metabolism of 3-ketoceramide in rat brain","volume":"30","author":"Shoyama","year":"1978","journal-title":"J. Neurochem."},{"key":"2022040211410523600_ref28","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1016\/j.bbamem.2006.08.009","article-title":"Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy","volume":"1758","author":"Zheng","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"2022040211410523600_ref29","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/S0014-5793(00)02332-2","article-title":"Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria","volume":"488","author":"Ardail","year":"2001","journal-title":"FEBS Lett."},{"key":"2022040211410523600_ref30","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1016\/j.immuni.2019.03.005","article-title":"Loss of neurological disease HSAN-I-associated gene SPTLC2 impairs CD8(+) T cell responses to infection by inhibiting T cell metabolic fitness","volume":"50","author":"Wu","year":"2019","journal-title":"Immunity"},{"key":"2022040211410523600_ref31","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1073\/pnas.1917525117","article-title":"Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid omega-O-acylceramide","volume":"117","author":"Yamamoto","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022040211410523600_ref32","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/jid.2013.517","article-title":"Intercellular skin barrier lipid composition and organization in netherton syndrome patients","volume":"134","author":"Smeden","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"2022040211410523600_ref33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jdermsci.2017.05.005","article-title":"Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition","volume":"88","author":"Danso","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"2022040211410523600_ref34","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/jid.2013.364","article-title":"Interferon-gamma decreases ceramides with long-chain fatty acids: possible involvement in atopic dermatitis and psoriasis","volume":"134","author":"Tawada","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"2022040211410523600_ref35","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.98006","article-title":"Lipid abnormalities in atopic skin are driven by type 2 cytokines","volume":"3","author":"Berdyshev","year":"2018","journal-title":"JCI Insight"},{"key":"2022040211410523600_ref36","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1194\/jlr.P030338","article-title":"Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients","volume":"53","author":"Janssens","year":"2012","journal-title":"J. Lipid Res."},{"key":"2022040211410523600_ref37","doi-asserted-by":"crossref","first-page":"15624","DOI":"10.1021\/la4037474","article-title":"Ceramides in the skin lipid membranes: length matters","volume":"29","author":"Skolova","year":"2013","journal-title":"Langmuir"},{"key":"2022040211410523600_ref38","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.bbalip.2013.11.006","article-title":"The important role of stratum corneum lipids for the cutaneous barrier function","volume":"1841","author":"Smeden","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"2022040211410523600_ref39","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00403-012-1286-5","article-title":"Variations in the ceramide profile in different seasons and regions of the body contribute to stratum corneum functions","volume":"305","author":"Ishikawa","year":"2013","journal-title":"Arch. Dermatol. Res."},{"key":"2022040211410523600_ref40","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0009-3084(75)90028-6","article-title":"Rearrangement of 3-ketoceramide","volume":"15","author":"Kishimoto","year":"1975","journal-title":"Chem. Phys. Lipids"},{"key":"2022040211410523600_ref41","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0009-3084(77)90034-2","article-title":"Beta-eliminative cleavage of 3-Ketocerebroside and 3-Ketosphingomyelin","volume":"20","author":"Iwamori","year":"1977","journal-title":"Chem. Phys. Lipids"},{"key":"2022040211410523600_ref42","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1016\/S0968-0896(02)00609-0","article-title":"Designing anticancer drugs via the achilles heel: ceramide, allylic ketones, and mitochondria","volume":"11","author":"Radin","year":"2003","journal-title":"Bioorg. Med. Chem."},{"key":"2022040211410523600_ref43","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1016\/j.bmc.2007.02.008","article-title":"Short-chain 3-ketoceramides, strong apoptosis inducers against human leukemia HL-60 cells","volume":"15","author":"Azuma","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"2022040211410523600_ref44","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/hmg\/ddr494","article-title":"Loss of ceramide synthase 3 causes lethal skin barrier disruption","volume":"21","author":"Jennemann","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2022040211410523600_ref45","doi-asserted-by":"crossref","first-page":"3312","DOI":"10.1194\/jlr.M040097","article-title":"1-O-acylceramides are natural components of human and mouse epidermis","volume":"54","author":"Rabionet","year":"2013","journal-title":"J. Lipid Res."},{"key":"2022040211410523600_ref46","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1074\/jbc.M610304200","article-title":"Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis","volume":"282","author":"Jennemann","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2022040211410523600_ref47","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. 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