Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway

Authors

Nicholas B. Blackburn, The University of Texas Rio Grande ValleyFollow
Juan M. Peralta, The University of Texas Rio Grande Valley
Satish Kumar, The University of Texas Rio Grande Valley
Ana C. Leandro, The University of Texas Rio Grande Valley
Marcio Almeida, The University of Texas Rio Grande Valley
Michael C. Mahaney, The University of Texas Rio Grande Valley
Thomas D. Dyer, The University of Texas Rio Grande Valley
Laura Almasy, The University of Texas Rio Grande Valley
John L. VandeBerg, The University of Texas Rio Grande Valley
Sarah Williams-Blangero, The University of Texas Rio Grande Valley
Ravindranath Duggirala, The University of Texas Rio Grande Valley
John Blangero, The University of Texas Rio Grande Valley
Joanne E. Curran, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

9-2019

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 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.

Comments

© 2019, Blackburn et al. Original published version available at https://doi.org/10.1194/jlr.P094433

Under a Creative Commons license

Recommended Citation

Blackburn, N. B., Michael, L. F., Meikle, P. J., Peralta, J. M., Mosior, M., McAhren, S., Bui, H. H., Bellinger, M. A., Giles, C., Kumar, S., Leandro, A. C., Almeida, M., Weir, J. M., Mahaney, M. C., Dyer, T. D., Almasy, L., VandeBerg, J. L., Williams-Blangero, S., Glahn, D. C., Duggirala, R., … Curran, J. E. (2019). Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway. Journal of lipid research, 60(9), 1630–1639. https://doi.org/10.1194/jlr.P094433

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Journal of Lipid Research

DOI

10.1194/jlr.P094433

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics