Year: 2019
Type: article
Study design: Observational Study
Abstract: 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 metabolic-related disorders and spur ongoing research of drug targets along this pathway.
Source: Journal of Lipid Research
DOI: 10.1194/jlr.p094433
Authors: 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 Duggirala, Mark Kowala, John Blangero, Joanne E. Curran
Institutions: The University of Texas Rio Grande Valley, Eli Lilly (United States), Baker Heart and Diabetes Institute, University of Tasmania, Menzies Institute for Medical Research, Children's Hospital of Philadelphia, University of Pennsylvania, Boston Children's Hospital, Hartford Hospital, Harvard University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: Eli Lilly and Company, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1181497844, G1327835149, Quantitative Trait Locus Mapping in Human Pedigrees, G220423607, Lipidomics of Obesity, Type 2 Diabetes and Cardiovascular Disease, Discovery of Functional Variants in Type 2 Diabetes Genes in Mexican Americans, G3257426095, G3804353902, G574117291, Construction of a Biomedical Research Facility at the U*, G8214780379, G9000019908, G9000033359, G9000073520, G9000096550, G9000110552, G9000121831, G9000127894, G9000146166, G9000182967, G9000244037, G9000278760, Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk
OpenAlex ID: W2951902916