Government of the United States of America - Center for Alzheimer's and Related Dementias (CARD); National Institutes of Health - Laboratory of Neurogenetics
Government of the United States of America - Center for Alzheimer's and Related Dementias (CARD); National Institutes of Health (NIH) - Cell Biology and Gene Expression Section
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.
Keywords: amyotrophic lateral sclerosis, genomics, de novo mutation, sphingolipid metabolism, SPTLC1, serine nutritional supplementation, deoxymethyl-sphinganine, individualized medicine
Janel, Johnson O. and Chia, Ruth and Kumaran, Ravindran and Alahmady, Nada and Abramzon, Yevgeniya and Faghri, Faraz and Renton, Alan and Topp, Simon D. and Pliner, Hannah A. and Gibbs, J. Raphael and Ding, Jinhui and Smith, Nathan and Landeck, Natalie and Nalls, Michael A. and Cookson, Mark R. and Pletnikova, Olga and Troncoso, Juan and Scholz, Sonja W. and Sabir, Marya S. and Ahmed, Sarah and Dalgard, Clifton L. and Troakes, Claire and Jones, Ashley R. and Shatunov, Aleksey and Iacoangeli, Alfredo and Al Khleifat, Ahmad and Ticozzi, Nicola and Silani, Vincenzo and Gellera, Cinzia and Blair, Ian P. and Dobson-Stone, Carol and Kwok, John B. and England, Bryce K. and Consortium, The International ALS Genomics and Consortium, The ITALSGEN and Consortium, The FALS Sequencing and Center, The American Genome and Tienari, Pentti and Stone, David J. and Morrison, Karen E. and Shaw, Pamela J. and Al-Chalabi, Ammar and Brown Jr., Robert H. and Brunetti, Maura and Calvo, Andrea and Mora, Gabriele and Gotkine, Marc and Shaw, Chris and Landers, John E. and Chiò, Adriano and Crawford, Thomas O. and Smith, Bradley and Traynor, Bryan J., Mutations in the Sphingolipid Pathway Gene
SPTLC1 are a Cause of Amyotrophic Lateral Sclerosis (June 5, 2019). Available at SSRN: https://ssrn.com/abstract=3399502 or http://dx.doi.org/10.2139/ssrn.3399502
This version of the paper has not been formally peer reviewed.
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