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Ceramide profiling of stratum corneum in Sjögren–Larsson syndrome

      Highlights

      • An SLS patient has a duplication and a missense mutation in ALDH3A2.
      • Acylceramide levels are reduced in the SLS patient.
      • The levels of several nonacylated ceramides are reduced in the SLS patient.
      • The fatty acid moiety is shortened in many ceramide classes in the SLS patient.

      Abstract

      Background

      Sjögren–Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation.

      Objectives

      To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS.

      Methods

      Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry.

      Results

      A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient’s ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes.

      Conclusion

      These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

      Abbreviations:

      SLS (Sjögren–Larsson syndrome), FALDH (fatty aldehyde dehydrogenase), FA (fatty acid), SC (stratum corneum), LCB (long-chain base), DS (dihydrosphingosine), S (sphingosine), P (phytosphingosine), H (6-hydroxysphingosine), SD (4,14-sphingadiene), N (nonhydroxy), A (α-hydroxy), O (ω-hydroxy), EO (esterified ω-hydroxy), P-O (protein-bound ω-hydroxy), acylceramide (ω-O-acylceramide), TLC (thin-layer chromatography), LC (liquid chromatography), MS/MS (tandem mass spectrometry), ER (endoplasmic reticulum)

      Keywords

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