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Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway


Blackburn, NB and Michael, LF and Meikle, PJ and Peralta, JM and Mosior, M and McAhren, S and Bui, HH and Bellinger, MA and Giles, C and Kumar, S and Leandro, AC and Almeida, M and Weir, JM and Mahaney, MC and Dyer, TD and Almasy, L and VandeBerg, JL and Williams-Blangero, S and Glahn, DC and Duggirala, R and Kowala, M and Blangero, J and Curran, JE, Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway, Journal of Lipid Research, 60, (9) pp. 1630-1639. ISSN 0022-2275 (2019) [Refereed Article]

Copyright Statement

Copyright 2019 Blackburn et al.

DOI: doi:10.1194/jlr.P094433


© 2019 Blackburn et al. 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.

Item Details

Item Type:Refereed Article
Keywords:genetics, genomics, lipidomics, sphingolipids
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genomics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Peralta, JM (Mr Juan Peralta Fernandez)
ID Code:136251
Year Published:2019
Web of Science® Times Cited:2
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-12-10
Last Modified:2020-03-27

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