Recurrentde-novo gain-of-functionmutation inSPTLC2confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specificgain-of-functionmutations inSPTLC1were identified in patients with juvenile form of ALS. SPTLC2encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex.MethodsWe used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants inSPTLC2. Thede-novostatus was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry.ResultsTwo unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novelde-novo SPTLC2mutation, c.203T>G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells.ConclusionsSpecificgain-of-functionmutations in both core subunits affect the homoeostatic control of SPT.SPTLC2represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.