# New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
## 4 Discussion
### Molecular Signature of p.(A20S)-SPTLC1-Mutant Lymphoblastoid Cells
Dihydroteridine reductase (QDPR; 2.69-fold increased) produces tetrahydroobiopterin (BH-4), an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. Recessive QDPR variants are leading to the manifestation of severe neurologic symptoms (MIM#261630) attributable to depletion of the neurotransmitter dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases that use BH-4 as cofactor. Thus, one might speculate that QDPR increase might correlate with compensatory neurotransmitter synthesis as the decrease of COMT (0.46-fold decreased), a key player of catecholamine neurotransmitters inactivation, also potentially does. PDZ and LIM domain protein 5 (PDLIM5) contributes to the regulation of dendritic spine morphogenesis in neurons ([[https://www.uniprot.org/uniprot/](https://www.uniprot.org/uniprot/)]([https://www.uniprot.org/uniprot/](https://www.uniprot.org/uniprot/)), accessed on 23 July 2018) and demonstrates a 1.97-fold increase in cells derived from our patient. Moreover, Bcl2-associated athanogene 2 (BAG2; 2.02-fold increased) acts as a regulator of p38-dependent tau kinase activity and phospho-tau degradation; tau-proteins were discussed as contributors for the manifestation of symptoms present in the clinical spectrum of SPTLC1-pathology [7; 32] and are known to trigger mitophagy to protect neurons against oxidative stress [33]. Mitochondrial vulnerability was indicated to be associated with the expression of SPTLC1-variant proteins under standard culture conditions in HEK293 cells [7]. A dysregulation of mitochondrial proteins in lymphoblastoid cells derived from our patient confirms a mitochondrial vulnerability (Supplementary Table S1). Here, aldehyde dehydrogenase X (ALDH1B1; 0.46-fold decreased) represents an interesting marker, as it is involved in lipid peroxidation and the metabolism of neurotransmitters. Previous studies on lymphoblastoid cells from HSAN1-patients already displayed mitochondrial abnormalities accompanied by dysregulation of mitochondrial proteins [2; 34]. However, comparative biochemical studies on lymphoblastoid cells derived from SPTLC1-related juvenile ALS patients with and without cognitive impairment are needed to prove the assumption of the modifying impact of threshold-expression of the above-discussed proteins in the clinical manifestation of diverse symptoms of SPTLC1-pathology. Taking the subcellular localization of SPTLC1 within the ER into consideration, previous studies on lymphocytes derived from HSAN1-patients reported notable changes in ER homeostasis associated with increase of ER-stress marker proteins, such as binding immunoglobulin protein (BiP) [2]. Our proteomic data did not hint toward unfolded protein response (UPR) activation in terms of an identified elevation of related proteins. In contrast, proteomic signature of our patient-derived cells indicated a decrease of ER-resident proteins such as protein O-glucosyltransferase 3 (POGLUT3; 0.46-fold decreased), a protein glucosyltransferase catalysing the transfer of glucose from uridine diphosphate (UDP)-glucose to a serine residue [35], and inositol 1,4,5-trisphosphate receptor type 2 (ITPR2; 0.41-fold decreased), a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular Ca\({}^{2+}\), in turn providing a direct biochemical link to perturbed Ca\({}^{2+}\) homeostasis as a well-known pathmechanism in the etiology of ALS [28]. Moreover, phosphatidylinositol glycan anchor biosynthesis class K (PIGK) along with phosphatidylinositol glycan anchor biosynthesis class S (PIGS) are decreased ER-resident proteins. Both are involved in glycosylphosphatidylinositol-anchor biosynthesis, which is part of glycolipid biosynthesis. A role of glycosphingolipids in neuronal polarity was already demonstrated in a C. elegans model of HSAN1 [36].