First published January 8, 2019 - More info
Background. Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies, however, the entire spectrum of sphingolipid metabolism disorders remained elusive. Methods. A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.Results. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous p.(Ala280Val) variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species which was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1 knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared to wild type cells which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. Conclusion. We report DEGS1 dysfunction as cause for a novel sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous system.Trial registration. Not applicable.Funding. RESOLVE: Project number 305707; SNF: Project 31003A_153390/1; Rare Disease Initiative Zurich.