title: Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Neuroscience Center, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02114, USA. feichler@partners.org
authors.forename: Florian S
authors.initials: FS
authors.lastname: Eichler
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.forename: Alex
authors.initials: A
authors.lastname: McCampbell
authors.forename: Dika
authors.initials: D
authors.lastname: Kuljis
authors.forename: Anke
authors.initials: A
authors.lastname: Penno
authors.forename: Daniel
authors.initials: D
authors.lastname: Vardeh
authors.forename: Eric
authors.initials: E
authors.lastname: Tamrazian
authors.forename: Kevin
authors.initials: K
authors.lastname: Garofalo
authors.forename: Ho-Joon
authors.initials: HJ
authors.lastname: Lee
authors.forename: Lohit
authors.initials: L
authors.lastname: Kini
authors.forename: Martin
authors.initials: M
authors.lastname: Selig
authors.forename: Matthew
authors.initials: M
authors.lastname: Frosch
authors.forename: Ken
authors.initials: K
authors.lastname: Gable
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Guiman
authors.initials: G
authors.lastname: Guan
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Harmon
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Dunn
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: 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
chemical_list: D021122:Protein Subunits; D013107:Sphingolipids; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse