HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship

Hum Mol Genet. 2016 Mar 1;25(5):853-65. doi: 10.1093/hmg/ddv611. Epub 2015 Dec 17.


Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare autosomal dominant inherited peripheral neuropathy caused by mutations in the SPTLC1 and SPTLC2 subunits of serine palmitoyltransferase (SPT). The mutations induce a permanent shift in the substrate preference from L-serine to L-alanine, which results in the pathological formation of atypical and neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Here we compared the enzymatic properties of 11 SPTLC1 and six SPTLC2 mutants using a uniform isotope labelling approach. In total, eight SPT mutants (STPLC1p.C133W, p.C133Y, p.S331F, p.S331Y and SPTLC2p.A182P, p.G382V, p.S384F, p.I504F) were associated with increased 1-deoxySL synthesis. Despite earlier reports, canonical activity with l-serine was not reduced in any of the investigated SPT mutants. Three variants (SPTLC1p.S331F/Y and SPTLC2p.I505Y) showed an increased canonical activity and increased formation of C20 sphingoid bases. These three mutations are associated with an exceptionally severe HSAN1 phenotype, and increased C20 sphingosine levels were also confirmed in plasma of patients. A principal component analysis of the analysed sphingoid bases clustered the mutations into three separate entities. Each cluster was related to a distinct clinical outcome (no, mild and severe HSAN1 phenotype). A homology model based on the protein structure of the prokaryotic SPT recapitulated the same grouping on a structural level. Mutations associated with the mild form clustered around the active site, whereas mutations associated with the severe form were located on the surface of the protein. In conclusion, we showed that HSAN1 mutations in SPT have distinct biochemical properties, which allowed for the prediction of the clinical symptoms on the basis of the plasma sphingoid base profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alanine / chemistry
  • Alanine / metabolism
  • Catalytic Domain
  • Child
  • Gas Chromatography-Mass Spectrometry
  • Gene Expression
  • HEK293 Cells
  • Hereditary Sensory and Autonomic Neuropathies / enzymology
  • Hereditary Sensory and Autonomic Neuropathies / genetics*
  • Hereditary Sensory and Autonomic Neuropathies / pathology
  • Humans
  • Isotope Labeling
  • Middle Aged
  • Models, Molecular
  • Mutation*
  • Phenotype
  • Principal Component Analysis
  • Recombinant Proteins / blood
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Serine / chemistry
  • Serine / metabolism
  • Serine C-Palmitoyltransferase / blood
  • Serine C-Palmitoyltransferase / chemistry
  • Serine C-Palmitoyltransferase / genetics*
  • Severity of Illness Index
  • Sphingolipids / blood
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Young Adult


  • Recombinant Proteins
  • Sphingolipids
  • Serine
  • SPTLC1 protein, human
  • SPTLC2 protein, human
  • Serine C-Palmitoyltransferase
  • Alanine