New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1

Genes (Basel). 2022 May 17;13(5):893. doi: 10.3390/genes13050893.

Abstract

Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphingoid base synthesis, causing a monogenic form of amyotrophic lateral sclerosis (ALS). It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment. A biochemical explanation for this clinical observation does not exist. By performing proteomic profiling on immortalized lymphoblastoid cells derived from one patient harbouring an alanine to serine amino acid substitution at position 20, we identified a subset of dysregulated proteins playing significant roles in neuronal homeostasis and might have a potential impact on the manifestation of symptoms. Notably, the identified p.(A20S)-SPTLC1 variant is associated with decrease of transcript and protein level. Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels. By performing coherent anti-Stokes Raman scattering microscopy, presence of protein and lipid aggregates could be excluded.

Keywords: HSAN1A; SPTLC1; juvenile ALS; proteomic profiling; serine palmitoyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Gain of Function Mutation*
  • Humans
  • Mutation
  • Proteomics
  • Serine C-Palmitoyltransferase* / chemistry
  • Serine C-Palmitoyltransferase* / genetics

Substances

  • SPTLC1 protein, human
  • Serine C-Palmitoyltransferase

Grants and funding

Parts of this study were financed in the framework of the NME-GPS project by the European Regional Development Fund (ERDF). We acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen. This work was supported by a grant from the French Muscular Dystrophy Association (AFM-Téléthon; #21644; grant to A.R.).