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

Abstract

Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific <i>gain-of-function</i> mutations in <i>SPTLC1</i> were identified in patients with juvenile form of ALS<i>. SPTLC2</i> encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in <i>SPTLC2</i>. The <i>de-novo</i> status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry. Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel <i>de-novo SPTLC2</i> 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. Specific <i>gain-of-function</i> mutations in both core subunits affect the homoeostatic control of SPT. <i>SPTLC2</i> 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.