Mutation screening of SPTLC1 and SPTLC2 in amyotrophic lateral sclerosis

In the current study, we explored the rare variants of SPTLC1 and SPTLC2 in a large Chinese ALS cohort. We identified the variant p.E406K (SPTLC1) reported in previous study, and three variants in the same amino acids as the variants reported in previous studies (p.Y509C, p.S331T, and p.R239Q). These finding broadened the current variant spectrum of SPTLC1 and SPTLC2 in ALS, and provided a foundation for further research.

SPTLC1 and SPTLC2 encode subunits 1 and 2 of SPT, an enzyme that catalyzes the biosynthesis of serine and palmitoyl CoA. Upregulation of SPT was suggested to play a role in apoptosis, suggesting its potential role in neurodegeneration. Variants in SPTLC1 and SPTLC2 were originally reported in patients with HSAN1, a rare peripheral neuropathy typically characterized by a slow and progressive sensory loss and the formation of perforating ulcers at the feet and hands. The variants could induce a permanent shift in the substrate preference from L-serine to L-alanine, which resulted in the pathological formation of atypical and neurotoxic 1-deoxy-sphingolipids [8]. Recently, several variants in SPTLC1 were identified as the disease cause for juvenile ALS. Compared with the variants for HSAN1, the variants for ALS disrupt the normal homeostatic regulation of SPT by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products [4]. Considering that alterations in SPT activity have been linked to neurodegeneration, and the close relation between SPTLC1 and SPTLC2, we also analyzed the rare protein-coding variants of SPTLC2.

In the current cohort, two patients with juvenile ALS carried variants p.Q229R (SPTLC1) and p.G435V (SPTLC2), both of which were absent in controls. WES suggested the two patients did not carry pathogenic variants in known ALS-related genes (https://alsod.ac.uk/). The patient with p.Q229R developed ALS at the age of 25, presenting with weakness in the proximal upper limb. He had tongue fasiculation, tongue atrophy and hyporeflexia. The variant p.G435V in SPTLC2 was suggested to cause HSAN1 [9]. This variant could lead to reduced effector-cytokine production and reduction of T cell proliferation, which was associated with a significant increase in apoptosis [9].

One patient carried the same variant p.E406K (SPTLC1) as reported in previous study [3]. This variant is rare in both the European and Chinese populations (MAF < 0.0001) based on data from gnomAD. Detection of the rare variant in patients from different ancestries suggested its potential role in ALS. However, considering the limited sample size, further replication was still warranted. Meanwhile, this variant was reported as potential cause for HSAN1 in ClinVar, though the clinical significance of this variant was still uncertain. Meanwhile, one ALS patient in our dataset carried p.T409M (SPTLC2), which was suggested to cause HSAN1 as well [8]. This variant was absent in controls, and predicted as damaging by eight prediction tools. Similarly, the rare variant p.S331Y (SPTLC1) was detected in both ALS and HSAN1 patients, suggesting potential overlapping pathogenesis between the two disorders. Incomplete penetrance or other modifier genes might contribute to the heterogeneous phenotypes for the same variant. Further exploration of the functional effect of these variants might provide additional insight.

In addition, three variants (p.Y509C, p.S331T, p.R239Q) in the same amino acids as previous variants were identified. Among the three variants, p.S331T and p.R239Q were absent in controls, while p.Y509C was ultra-rare (MAF < 0.001). All the three variants were predicted as damaging by at least 5 prediction tools, and had high GERP scores (5.25, 4.52 and 5.3). All the three patients were with adult-onset ALS, suggesting potential association between specific variants of SPTLC1 and adult-onset ALS, which needs further exploration.

Though several rare variants of SPCLC1 and SPTLC2 were detected in patients with ALS, whether these variants were disease cause of these patients was unknown. Meanwhile, we did not identify an association between the rare variants and disease risk at both variant and gene levels, disapproving the genetic role of these two genes in ALS to some extent. However, the results should be interpreted with caution since the sample size was relatively small, and an association is hard to detect for rare variants in case–control designed studies, especially in the context of etiological heterogeneity and incomplete penetrance. Additionally, the rare variants of SPTLC1 were detected in juvenile ALS in the original study, while in the current cohort most of the patients were adult-onset. Therefore, further replication in juvenile ALS with larger sample size is still necessary.

In conclusion, we systematically analyzed the rare variants of SPLTC1 and SPTLC2 in ALS with association analyses at variant and gene levels. Our work broadened the current variant spectrum of SPTLC1 and SPTLC2 in ALS, and provided a foundation for future research on these two genes in ALS.

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