Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1.
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1(C133W)) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1(C133W), but not in the wild-type, double-transgenic tgSPTLC1(WT + C133W) or SPTLC1(+/-) mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.
Eichler
Florian S
FS
Massachusetts General Hospital Neuroscience Center, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02114, USA. feichler@partners.org
Hornemann
Thorsten
T
McCampbell
Alex
A
Kuljis
Dika
D
Penno
Anke
A
Vardeh
Daniel
D
Tamrazian
Eric
E
Garofalo
Kevin
K
Lee
Ho-Joon
HJ
Kini
Lohit
L
Selig
Martin
M
Frosch
Matthew
M
Gable
Ken
K
von Eckardstein
Arnold
A
Woolf
Clifford J
CJ
Guan
Guiman
G
Harmon
Jeffrey M
JM
Dunn
Teresa M
TM
Brown
Robert H
RH
D000818:Animals; D006224:Cricetinae; D015870:Gene Expression; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051102:Serine C-Palmitoyltransferase / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism* / Q000633:toxicity
D021122:Protein Subunits; D013107:Sphingolipids; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse