Article Text
PDF
Abstract
Background Amyotrophic 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.
Methods We 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.
Results Two 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.
Conclusions Specific 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.
- MOTOR NEURON DISEASE
- NEUROGENETICS
- ALS
- BIOCHEMISTRY
- NEUROMUSCULAR
Statistics from Altmetric.com
Footnotes
Twitter @MuseerSphinx
MFD, DB, MAL, ANıBşa, TH and SZ contributed equally.
Contributors The patients were examined by EB, PO and NB (patient 1) as well as RO, SD and ARF (patient 2). Whole-genome sequencing was performed and sequencing data aligned by MS, SC and MCD. Molecular genetic analyses were conducted by MFD, DB, AR, ML and RL. Genotype-phenotype correlations were done by MFD, DB, RO, SD, NB and CGB. Analyses of the patient’s plasma sphingolipid profile and further in vitro studies were performed by MAL, TH, KG and TD. SZ, NB, CGB and TH conceptualised and supervised the project. MFD, DB, and MAL drafted the manuscript. All authors critically reviewed the manuscript. Edits were applied by MFD.
Funding This study was funded by Swiss National Science Foundation (31003A_179371), NIH (R01NS105755), DFG (DO 2386/1-1), European Joint Programme on Rare Diseases (32ER30_187505), DFG, German Research Foundation (441409627).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.