Phd Student German Cancer Research Center (DKFZ), Heidelberg University Heidelberg, Baden-Wurttemberg, Germany
Robert Pilz (German Cancer Research Center (DKFZ), Heidelberg University)| Lukáš Opálka (Charles University, German Cancer Research Center (DKFZ))| Adam Majcher (German Cancer Research Center (DKFZ), Charles University)| Elisabeth Grimm (German Cancer Research Center (DKFZ), Heidelberg University)| Lionel Van Maldergem (Université de Franche-Comté, University Hospital Besançon)| François Aubin (CHU et UFR Santé)| Anne-Claire Bursztejn (University Hospital Nancy)| Elise Brischoux-Boucher (Université de Franche-Comté)| Judith Fischer (University of Freiburg)| Roger Sandhoff (German Cancer Research Center (DKFZ))
Functional skin barrier requires sphingolipid homeostasis. 3-ketodihydrosphingosine reductase or KDSR is a key enzyme of sphingolipid anabolism and catalyzes the reduction of 3-ketodihydrosphingosine to sphinganine. Biallelic mutations in the KDSR gene may cause skin pathologies of the erythrokeratoderma spectrum. The underlying molecular changes in sphingolipid metabolism remain largely unexplored.
We report a new patient with compound heterozygous mutations in KDSR. The patient was born with generalized harlequin ichthyosis, which progressed into palmoplantar keratoderma. In stratum corneum of this and another patient with KDSR mutations we identified skin ceramides with an unusual sphingoid base. These unobserved keto-type ceramides were found in lesional and non-lesional skin areas and accounted for up to 10% of the measured ceramide species. We observed on average a shorter chain length of sphingoid bases and associated fatty acids in both patients.
Formation of keto-type ceramides is probably due to the utilization of accumulating 3-ketodihydrosphingosine as an alternative substrate by ceramide synthases, which highlights the importance of tight intermediate regulation during sphingolipid anabolism. It is conceivable that the observed alterations affect lamellar lipid organization leading to defective skin barrier and keratinocyte differentiation.