Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway

Nicholas B. Blackburn, Laura F. Michael, Peter J. Meikle, Juan M. Peralta, Marian Mosior, Scott McAhren, Hai H. Bui, Melissa A. Bellinger, Corey Giles, Satish Kumar, Ana C. Leandro, Marcio Almeida, Jacquelyn M. Weir, Michael C. Mahaney, Thomas D. Dyer, Laura Almasy, John L. VandeBerg, Sarah Williams-Blangero, David C. Glahn, Ravindranath DuggiralaMark Kowala, John Blangero, Joanne E. Curran

    Research output: Contribution to journalArticlepeer-review

    9 Scopus citations


    The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolicrelated disorders and spur ongoing research of drug targets along this pathway.

    Original languageEnglish (US)
    Pages (from-to)1630-1639
    Number of pages10
    JournalJournal of lipid research
    Issue number9
    StatePublished - 2019


    • Genetics
    • Genomics
    • Lipidomics
    • Sphingolipids

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology
    • Cell Biology


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