Gene of the Month – January: DEGS1

Delta(4)-dihydroceramide desaturase, the protein encoded by DEGS1, acts as a catalyzing enzyme in the synthesis of ceramide, a basic building block of sphingolipids. Sphingolipids are essential constituents of biological membranes and play an important role in fundamental cellular processes including cell differentiation, proliferation and apoptosis. In nerve cells, they are involved in myelin sheath formation and participate in neuronal signaling pathways. Perturbations in sphingolipid synthesis or degradation result in several neurological diseases. However, the entire range of sphingolipid metabolism disorders has not yet been fully elucidated.

Using an innovative approach combining genomic and lipidomic investigations, researchers from Germany and Switzerland have now for the first time identified a variant of DEGS1 implicated in a monogenic human disorder. In a patient affected by a multisystem disorder with hypomyelination and degeneration of the central and peripheral nervous system, they found a pathogenic homozygous missense variant in DEGS1. The results of their study, published in the Journal of Clinical Investigation, show that the mutation leads to an increase in specific dihydrosphingolipids in the plasma and to the formation of a novel, atypical and potentially neurotoxic sphingolipid metabolite. In parallel, in a study published in the same issue of the journal, another international collaboration of researchers revealed homozygous and compound-heterozygous DEGS1 mutations as the genetic cause of hypomyelinating leukodystrophy.