SPTLC1 and amyotrophic lateral sclerosis: The amino acids in the TMD could be important for the interaction with ORMDL proteins, but as they could also be essential for ER targeting and membrane integration of SPTLC1, we first set out to determine the localization and membrane association of a subset of pathogenic SPTLC1 variants in detail, namely the ALS variants Y23F, L39del, F40S41del, a variant missing the whole of exon 2 (ex2del) induced by aberrant splicing in an A20S patient (4), and the HSAN1 variants C133W and S331F (Figure 1A).