Janel, JO, Chia, R, Kumaran, R et al. (50 more authors) (Submitted: 2019) Mutations in the sphingolipid pathway gene SPTLC1 are a cause of amyotrophic lateral sclerosis. SSRN. (Submitted)
Abstract
SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A. Using exome sequencing, we identified a de novo coding variant in SPTLC1 in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS), and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. We also found SPTLC1 mutations in 0.34% of 5,607 ALS cases, and immunohistochemically confirmed the expression of SPTLC1 in spinal cord motor neurons, supporting their role in the pathogenesis of this fatal neurodegenerative disease. Toxicity of deoxymethyl-sphinganine was demonstrated in HEK293FT cells, and could be corrected by L-serine supplementation. Our data broaden the phenotype associated with SPTLC1. Furthermore, nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in SPTLC1.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 SSRN. |
Keywords: | amyotrophic lateral sclerosis; genomics; de novo mutation; sphingolipid metabolism; SPTLC1; serine nutritional supplementation; deoxymethyl-sphinganine; individualized medicine |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 25 Mar 2022 15:13 |
Last Modified: | 25 Mar 2022 15:13 |
Status: | Submitted |
Publisher: | Cell Press (Elsevier) |
Identification Number: | 10.2139/ssrn.3399502 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:184937 |