Ceramide profiling of stratum corneum in Sjögren–Larsson syndrome


      • 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.



      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.


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


      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.


      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.


      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.


      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)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Selmanowitz V.J.
        • Porter M.J.
        The Sjögren-Larsson syndrome.
        Am. J. Med. 1967; 42: 412-422
        • Rizzo W.B.
        Sjögren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency.
        Mol. Genet. Metab. 2007; 90: 1-9
      1. V. Oji, G. Tadini, M. Akiyama, C. Blanchet Bardon, C. Bodemer, E. Bourrat, et al., Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009, J. Am. Acad. Dermatol., vol. 63, 2010, pp. 607–41.

        • Takeichi T.
        • Akiyama M.
        Inherited ichthyosis: non-syndromic forms.
        J. Dermatol. 2016; 43: 242-251
        • De Laurenzi V.
        • Rogers G.R.
        • Hamrock D.J.
        • Marekov L.N.
        • Steinert P.M.
        • Compton J.G.
        • et al.
        Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene.
        Nat. Genet. 1996; 12: 52-57
        • Feingold K.R.
        • Elias P.M.
        Role of lipids in the formation and maintenance of the cutaneous permeability barrier.
        Biochim. Biophys. Acta. 1841; 2014: 280-294
        • van Smeden J.
        • Janssens M.
        • Gooris G.S.
        • Bouwstra J.A.
        The important role of stratum corneum lipids for the cutaneous barrier function.
        Biochim. Biophys. Acta. 1841; 2014: 295-313
        • Kihara A.
        Synthesis and degradation pathways, functions, and pathology of ceramides and epidermal acylceramides.
        Prog. Lipid Res. 2016; 63: 50-69
        • Jojima K.
        • Edagawa M.
        • Sawai M.
        • Ohno Y.
        • Kihara A.
        Biosynthesis of the anti-lipid-microdomain sphingoid base 4,14-sphingadiene by the ceramide desaturase FADS3.
        FASEB J. 2020; 34: 3318-3335
        • Kawana M.
        • Miyamoto M.
        • Ohno Y.
        • Kihara A.
        Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS.
        J. Lipid Res. 2020; 61: 884-895
        • Muñoz-Garcia A.
        • Thomas C.P.
        • Keeney D.S.
        • Zheng Y.
        • Brash A.R.
        The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier.
        Biochim. Biophys. Acta. 1841; 2014: 401-408
        • Akiyama M.
        Acylceramide is a key player in skin barrier function: insight into the molecular mechanisms of skin barrier formation and ichthyosis pathogenesis.
        FEBS J. 2021; 288: 2119-2130
        • Paige D.G.
        • Morse-Fisher N.
        • Harper J.I.
        Quantification of stratum corneum ceramides and lipid envelope ceramides in the hereditary ichthyoses.
        Br. J. Dermatol. 1994; 131: 23-27
        • Nakajima K.
        • Sano S.
        • Uchida Y.
        • Akiyama M.
        • Morita Y.
        • Shimizu H.
        Altered lipid profiles in the stratum corneum of Sjögren-Larsson syndrome.
        J. Dermatol. Sci. 2011; 63: 64-66
        • Yamamoto M.
        • Sassa T.
        • Kyono Y.
        • Uemura H.
        • Kugo M.
        • Hayashi H.
        • et al.
        Comprehensive stratum corneum ceramide profiling reveals reduced acylceramides in ichthyosis patient with CERS3 mutations.
        J. Dermatol. 2021; 48: 447-456
        • Ito Y.
        • Takeichi T.
        • Ikeda K.
        • Tanahashi K.
        • Yoshikawa T.
        • Murase Y.
        • et al.
        Updated allele frequencies of SERPINB7 founder mutations in Asian patients with Nagashima-type palmoplantar keratosis/keratoderma.
        J. Dermatol. Sci. 2021; 103: 116-119
        • Rizzo W.B.
        • Carney G.
        • Lin Z.
        The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene.
        Am. J. Hum. Genet. 1999; 65: 1547-1560
        • Richards S.
        • Aziz N.
        • Bale S.
        • Bick D.
        • Das S.
        • Gastier-Foster J.
        • et al.
        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.
        Genet. Med. 2015; 17: 405-424
        • Marekov L.N.
        • Steinert P.M.
        Ceramides are bound to structural proteins of the human foreskin epidermal cornified cell envelope.
        J. Biol. Chem. 1998; 273: 17763-17770
        • Takeichi T.
        • Hirabayashi T.
        • Miyasaka Y.
        • Kawamoto A.
        • Okuno Y.
        • Taguchi S.
        • et al.
        SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation.
        J. Clin. Invest. 2020; 130: 890-903
        • Sassa T.
        • Ohno Y.
        • Suzuki S.
        • Nomura T.
        • Nishioka C.
        • Kashiwagi T.
        • et al.
        Impaired epidermal permeability barrier in mice lacking Elovl1, the gene responsible for very-long-chain fatty acid production.
        Mol. Cell. Biol. 2013; 33: 2787-2796
        • Yamamoto H.
        • Hattori M.
        • Chamulitrat W.
        • Ohno Y.
        • Kihara A.
        Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid ω-O-acylceramide.
        Proc. Natl. Acad. Sci. USA. 2020; 117: 2914-2922
        • Miyamoto M.
        • Itoh N.
        • Sawai M.
        • Sassa T.
        • Kihara A.
        Severe skin permeability barrier dysfunction in knockout mice deficient in a fatty acid ω-hydroxylase crucial to acylceramide production.
        J. Invest. Dermatol. 2020; 140: 319-326
        • Ohno Y.
        • Nakamichi S.
        • Ohkuni A.
        • Kamiyama N.
        • Naoe A.
        • Tsujimura H.
        • et al.
        Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation.
        Proc. Natl. Acad. Sci. USA. 2015; 112: 7707-7712
        • Nojiri K.
        • Fudetani S.
        • Arai A.
        • Kitamura T.
        • Sassa T.
        • Kihara A.
        Impaired skin barrier function due to reduced ω-O-acylceramide levels in a mouse model of Sjögren-Larsson syndrome.
        Mol. Cell. Biol. 2021; 41e0035221
        • Ohno Y.
        • Kamiyama N.
        • Nakamichi S.
        • Kihara A.
        PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide.
        Nat. Commun. 2017; 8: 14610
        • Ohno Y.
        • Nara A.
        • Nakamichi S.
        • Kihara A.
        Molecular mechanism of the ichthyosis pathology of Chanarin-Dorfman syndrome: stimulation of PNPLA1-catalyzed ω-O-acylceramide production by ABHD5.
        J. Dermatol. Sci. 2018; 92: 245-253
        • Grall A.
        • Guaguere E.
        • Planchais S.
        • Grond S.
        • Bourrat E.
        • Hausser I.
        • et al.
        PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.
        Nat. Genet. 2012; 44: 140-147
        • Lord C.C.
        • Thomas G.
        • Brown J.M.
        Mammalian alpha beta hydrolase domain (ABHD) proteins: lipid metabolizing enzymes at the interface of cell signaling and energy metabolism.
        Biochim. Biophys. Acta. 1831; 2013: 792-802
        • Brown A.L.
        • Mark Brown J.
        Critical roles for α/β hydrolase domain 5 (ABHD5)/comparative gene identification-58 (CGI-58) at the lipid droplet interface and beyond.
        Biochim. Biophys. Acta. 1862; 2017: 1233-1241
        • Hirabayashi T.
        • Murakami M.
        • Kihara A.
        The role of PNPLA1 in ω-O-acylceramide synthesis and skin barrier function.
        Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 1864; 2019: 869-879
        • Ternes P.
        • Franke S.
        • Zahringer U.
        • Sperling P.
        • Heinz E.
        Identification and characterization of a sphingolipid ∆4-desaturase family.
        J. Biol. Chem. 2002; 277: 25512-25518
        • Alderson N.L.
        • Rembiesa B.M.
        • Walla M.D.
        • Bielawska A.
        • Bielawski J.
        • Hama H.
        The human FA2H gene encodes a fatty acid 2-hydroxylase.
        J. Biol. Chem. 2004; 279: 48562-48568
        • Kanetake T.
        • Sassa T.
        • Nojiri K.
        • Sawai M.
        • Hattori S.
        • Miyakawa T.
        • et al.
        Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.
        FASEB J. 2019; 33: 928-941
        • Zöller I.
        • Meixner M.
        • Hartmann D.
        • Büssow H.
        • Meyer R.
        • Gieselmann V.
        • et al.
        Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration.
        J. Neurosci. 2008; 28: 9741-9754
        • Dick K.J.
        • Eckhardt M.
        • Paisan-Ruiz C.
        • Alshehhi A.A.
        • Proukakis C.
        • Sibtain N.A.
        • et al.
        Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35).
        Hum. Mutat. 2010; 31: E1251-E1260
        • Potter K.A.
        • Kern M.J.
        • Fullbright G.
        • Bielawski J.
        • Scherer S.S.
        • Yum S.W.
        • et al.
        Central nervous system dysfunction in a mouse model of FA2H deficiency.
        Glia. 2011; 59: 1009-1021
        • Kihara A.
        Very long-chain fatty acids: elongation, physiology and related disorders.
        J. Biochem. 2012; 152: 387-395
        • Aldahmesh M.A.
        • Mohamed J.Y.
        • Alkuraya H.S.
        • Verma I.C.
        • Puri R.D.
        • Alaiya A.A.
        • et al.
        Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia.
        Am. J. Hum. Genet. 2011; 89: 745-750
        • Kutkowska-Kaźmierczak A.
        • Rydzanicz M.
        • Chlebowski A.
        • Kłosowska-Kosicka K.
        • Mika A.
        • Gruchota J.
        • et al.
        Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.
        J. Med. Genet. 2018; 55: 408-414
        • Mueller N.
        • Sassa T.
        • Morales-Gonzalez S.
        • Schneider J.
        • Salchow D.J.
        • Seelow D.
        • et al.
        De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy.
        J. Med. Genet. 2019; 56: 164-175
        • Takahashi T.
        • Mercan S.
        • Sassa T.
        • Akçapınar G.B.
        • Yararbaş K.
        • Süsgün S.
        • et al.
        Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1.
        Brain Dev. 2022; 44: 391-400
        • Ohno Y.
        • Suto S.
        • Yamanaka M.
        • Mizutani Y.
        • Mitsutake S.
        • Igarashi Y.
        • et al.
        ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
        Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444
        • Kihara A.
        Sphingosine 1-phosphate is a key metabolite linking sphingolipids to glycerophospholipids.
        Biochim. Biophys. Acta. 1841; 2014: 766-772
        • Edagawa M.
        • Sawai M.
        • Ohno Y.
        • Kihara A.
        Widespread tissue distribution and synthetic pathway of polyunsaturated C24:2 sphingolipids in mammals.
        Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 1863; 2018: 1441-1448
        • Suzuki M.
        • Ohno Y.
        • Kihara A.
        Whole picture of human stratum corneum ceramides, including the chain-length diversity of long-chain bases.
        J. Lipid Res. 2022; 63100235
        • Schumacher F.
        • Neuber C.
        • Finke H.
        • Nieschalke K.
        • Baesler J.
        • Gulbins E.
        • et al.
        The sphingosine 1-phosphate breakdown product, (2E)-hexadecenal, forms protein adducts and glutathione conjugates in vitro.
        J. Lipid Res. 2017; 58: 1648-1660
        • Ikeda M.
        • Kihara A.
        • Igarashi Y.
        Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol.
        Biochem. Biophys. Res. Commun. 2004; 325: 338-343
        • Sassa T.
        • Wakashima T.
        • Ohno Y.
        • Kihara A.
        Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid.
        J. Lipid Res. 2014; 55: 524-530
        • Zhu G.
        • Koszelak-Rosenblum M.
        • Connelly S.M.
        • Dumont M.E.
        • Malkowski M.G.
        The crystal structure of an integral membrane fatty acid α-hydroxylase.
        J. Biol. Chem. 2015; 290: 29820-29833