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HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship
Heiko Bode1, Florence Bourquin2, Saranya Suriyanarayanan3
1Institute for Clinical Chemistry, University Hospital Zurich, Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
Human Molecular Genetics
|December 19, 2015
Summary
Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is caused by mutations in serine palmitoyltransferase (SPT). These mutations lead to toxic lipid production, with distinct biochemical properties correlating to HSAN1 severity.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare inherited peripheral neuropathy.
- It is caused by mutations in SPTLC1 and SPTLC2 subunits of serine palmitoyltransferase (SPT).
- Mutations cause a shift in substrate preference, leading to neurotoxic 1-deoxy-sphingolipids (1-deoxySL).
Purpose of the Study:
- To compare the enzymatic properties of HSAN1-associated SPTLC1 and SPTLC2 mutants.
- To correlate biochemical properties with clinical HSAN1 phenotypes.
- To investigate the structural basis of mutation-induced pathogenicity.
Main Methods:
- Enzymatic assays of 17 SPT mutants (11 SPTLC1, 6 SPTLC2) using uniform isotope labeling.
- Analysis of sphingoid base profiles in patient plasma.
- Principal component analysis and homology modeling of SPT structure.
Main Results:
- Eight SPT mutants showed increased 1-deoxySL synthesis.
- No mutants exhibited reduced canonical activity with L-serine.
- Three variants (SPTLC1p.S331F/Y, SPTLC2p.I505Y) showed increased canonical activity and C20 sphingoid base formation, correlating with severe HSAN1.
- Plasma sphingoid base profiles clustered mutations into three groups linked to distinct clinical outcomes (no, mild, severe HSAN1).
Conclusions:
- HSAN1-associated SPT mutations possess distinct biochemical properties.
- Plasma sphingoid base profiles can predict HSAN1 clinical symptoms.
- Structural analysis reveals distinct clustering of mild and severe mutation sites relative to the SPT active site.
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