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dc.contributor.authorLone, Museer A.pt_BR
dc.contributor.authorAaltonen, Mari J.pt_BR
dc.contributor.authorZidell , Alizapt_BR
dc.contributor.authorPedro, Helio F.pt_BR
dc.contributor.authorSaute, Jonas Alex Moralespt_BR
dc.contributor.authorMathew, Shalettpt_BR
dc.contributor.authorMohassel, Payampt_BR
dc.contributor.authorBönnemann, Carsten G.pt_BR
dc.contributor.authorShoubridge, Eric A.pt_BR
dc.contributor.authorHornemann, Thorstenpt_BR
dc.date.accessioned2022-10-27T04:52:22Zpt_BR
dc.date.issued2022pt_BR
dc.identifier.issn0021-9738pt_BR
dc.identifier.urihttp://hdl.handle.net/10183/250482pt_BR
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.en
dc.format.mimetypeapplication/pdfpt_BR
dc.language.isoengpt_BR
dc.relation.ispartofThe Journal of clinical investigation. New York, NY. Vol. 132, no. 18 (Nov. 2011), e161908, p. 1-12pt_BR
dc.rightsOpen Accessen
dc.subjectEsclerose lateral amiotróficapt_BR
dc.subjectALSen
dc.subjectCarbohydrate metabolismen
dc.subjectMetabolismo dos carboidratospt_BR
dc.subjectDoenças neuromuscularespt_BR
dc.subjectNeuromuscular diseaseen
dc.subjectNeuroscienceen
dc.subjectNeurociênciaspt_BR
dc.titleSPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteinspt_BR
dc.typeArtigo de periódicopt_BR
dc.identifier.nrb001152103pt_BR
dc.type.originEstrangeiropt_BR


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