Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 95; no. 3; pp. 201 - 205
• Main Authors: Dohrn, Maike F, Beijer, Danique, Lone, Museer A, Bayraktar, Elif, Oflazer, Piraye, Orbach, Rotem, Donkervoort, Sandra, Foley, A Reghan, Rose, Aubrey, Lyons, Michael, Louie, Raymond J, Gable, Kenneth, Dunn, Teresa, Chen, Sitong, Danzi, Matt C, Synofzik, Matthis, Bönnemann, Carsten G, Nazlı Başak, A, Hornemann, Thorsten, Zuchner, Stephan
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.03.2024; BMJ Publishing Group LTD
• Subjects: Age; ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Atrophy; BIOCHEMISTRY; Ceramides; Chromatography; Enzymes; Families & family life; Family medical history; Gain of Function Mutation; Genomes; Humans; Metabolic disorders; MOTOR NEURON DISEASE; Motor neurone disease; Mutation; Mutation - genetics; Neurogenetics; NEUROMUSCULAR; Neuromuscular diseases; Neurotoxicity; Ostomy; Patients; Plasma; Principal components analysis; Scientific imaging; Serine C-Palmitoyltransferase - chemistry; Serine C-Palmitoyltransferase - genetics; Sphingolipids; Variance analysis; ALS; NEUROMUSCULAR; NEUROGENETICS; MOTOR NEURON DISEASE; BIOCHEMISTRY
• ISSN: 0022-3050; 1468-330X; 1468-330X
• DOI: 10.1136/jnnp-2023-332130

BackgroundAmyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes 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 in SPTLC2. The de-novo status 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 novel de-novo SPTLC2 mutation, 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.ConclusionsSpecific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents 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.