Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids.
HSAN1 is an inherited neuropathy found to be associated with several missense mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Here we show that the HSAN1 mutations induce a shift in the substrate specificity of SPT, which leads to the formation of the two atypical deoxy-sphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C(1) hydroxyl group of sphinganine and can therefore neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell, as demonstrated in HEK293 cells overexpressing mutant SPTLC1 and lymphoblasts of HSAN1 patients. Elevated DSB levels were also found in the plasma of HSAN1 patients and confirmed in three groups of HSAN1 patients with different SPTLC1 mutations. The DSBs show pronounced neurotoxic effects on neurite formation in cultured sensory neurons. The neurotoxicity co-occurs with a disturbed neurofilament structure in neurites when cultured in the presence of DSBs. Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.
Penno
Anke
A
Institute for Clinical Chemistry, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.
Reilly
Mary M
MM
Houlden
Henry
H
Laurá
Matilde
M
Rentsch
Katharina
K
Niederkofler
Vera
V
Stoeckli
Esther T
ET
Nicholson
Garth
G
Eichler
Florian
F
Brown
Robert H
RH
von Eckardstein
Arnold
A
Hornemann
Thorsten
T
D000818:Animals; D002642:Chick Embryo; D037341:Fumonisins / Q000737:chemistry; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008214:Lymphocytes / Q000166:cytology; D008954:Models, Biological; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D051102:Serine C-Palmitoyltransferase / Q000235:genetics* / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*; D013379:Substrate Specificity
D037341:Fumonisins; D008055:Lipids; D009498:Neurotoxins; D013107:Sphingolipids; C056933:fumonisin B1; C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase