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01-06-2019 | Original Paper

A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C

Authors: Saranya Suriyanarayanan, Alaa Othman, Bianca Dräger, Anja Schirmacher, Peter Young, Lejla Mulahasanovic, Konstanze Hörtnagel, Saskia Biskup, Arnold von Eckardstein, Thorsten Hornemann, Museer A. Lone

Published in: NeuroMolecular Medicine | Issue 2/2019

Abstract

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare, autosomal dominantly inherited, slowly progressive and length-dependent axonal peripheral neuropathy. HSAN1 is associated with several mutations in serine-palmitoyltransferase (SPT), the first enzyme in the de novo sphingolipid biosynthetic pathway. HSAN1 mutations alter the substrate specificity of SPT, which leads to the formation of 1-deoxysphingolipids, an atypical and neurotoxic subclass of sphingolipids. This study describes the clinical and neurophysiological phenotype of a German family with a novel SPTCL2 mutation (c.529A > G; N177D) associated with HSAN1 and the biochemical characterization of this mutation.) The mutaion was identified in five family members that segregated with the diesease. Patients were characterized genetically and clinically for neurophysiological function. Their plasma sphingolipid profiles were analyzed by LC–MS. The biochemical properties of the mutation were characterized in a cell-based activity assay. Affected family members showed elevated 1-deoxysphingolipid plasma levels. HEK293 cells expressing the N177D SPTLC2 mutant showed increased de novo 1-deoxysphingolipid formation, but also displayed elevated canonical SPT activity and increased C20 sphingoid base production. This study identifies the SPTLC2 N177D variant as a novel disease-causing mutation with increased 1-deoxySL formation and its association with a typical HSAN1 phenotype.

Auer-Grumbach, M. (2013). Hereditary sensory and autonomic neuropathies. Handbook of Clinical Neurology, 115, 893–906. https://doi.org/10.1016/b978-0-444-52902-2.00050-3.CrossRefPubMed

Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., et al. (2013). Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. European Journal of Medical Genetics, 56(5), 266–269. https://doi.org/10.1016/j.ejmg.2013.02.002.CrossRefPubMedPubMedCentral

Auranen, M., Toppila, J., Suriyanarayanan, S., Lone, M. A., Paetau, A., Tyynismaa, H., et al. (2017). Clinical and metabolic consequences of l-serine supplementation in hereditary sensory and autonomic neuropathy type 1C. Cold Spring Harbor Molecular Case Studies. https://doi.org/10.1101/mcs.a002212.CrossRefPubMedPubMedCentral

Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., et al. (2016). HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship. Human Molecular Genetics, 25(5), 853–865. https://doi.org/10.1093/hmg/ddv611.CrossRefPubMed

Breslow, D. K., Collins, S. R., Bodenmiller, B., Aebersold, R., Simons, K., Shevchenko, A., et al. (2010). Orm family proteins mediate sphingolipid homeostasis. Nature, 463, 1048–1053. https://doi.org/10.1038/nature08787.CrossRefPubMedPubMedCentral

Davis, D. L., Gable, K., Suemitsu, J., Dunn, T. M., & Wattenberg, B. W. (2019). The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.ra118.007291.CrossRefPubMed

Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., & Nicholson, G. A. (2001). Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nature Genetics, 27(3), 309–312. https://doi.org/10.1038/85879.CrossRefPubMed

Dohrn, M. F., Glockle, N., Mulahasanovic, L., Heller, C., Mohr, J., Bauer, C., et al. (2017). Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies. Journal of Neurochemistry, 143(5), 507–522. https://doi.org/10.1111/jnc.14217.CrossRefPubMed

Dyck, P. J. (1993). Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In P. J. Dyck, K. P. Thomas, J. W. Griffin, P. A. Low, & J. F. Poduslo (Eds.), Peripheral Neuropathy (3rd ed., pp. 1065–1093). Philladelphia: Saunders.

Edvardson, S., Cinnamon, Y., Jalas, C., Shaag, A., Maayan, C., Axelrod, F. B., et al. (2012). Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. Annals of Neurology, 71(4), 569–572. https://doi.org/10.1002/ana.23524.CrossRefPubMed

Eichler, F. S., Hornemann, T., McCampbell, A., Kuljis, D., Penno, A., Vardeh, D., et al. (2009). Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1. The Journal of Neuroscience, 29(46), 14646–14651. https://doi.org/10.1523/jneurosci.2536-09.2009.CrossRefPubMedPubMedCentral

Ernst, D., Murphy, S. M., Sathiyanadan, K., Wei, Y., Othman, A., Laura, M., et al. (2015). Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity. NeuroMolecular Medicine, 17(1), 47–57. https://doi.org/10.1007/s12017-014-8339-1.CrossRefPubMedPubMedCentral

Fridman, V., Suriyanarayanan, S., Novak, P., David, W., Macklin, E. A., McKenna-Yasek, D., et al. (2019). Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. Neurology, 92(4), e359–e370. https://doi.org/10.1212/wnl.0000000000006811.CrossRefPubMedPubMedCentral

Garofalo, K., Penno, A., Schmidt, B. P., Lee, H. J., Frosch, M. P., von Eckardstein, A., et al. (2011). Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. Journal of Clinical Investigation, 121(12), 4735–4745. https://doi.org/10.1172/jci57549.CrossRefPubMed

Geraldes, R., de Carvalho, M., Santos-Bento, M., & Nicholson, G. (2004). Hereditary sensory neuropathy type 1 in a Portuguese family-electrodiagnostic and autonomic nervous system studies. Journal of the Neurological Sciences, 227, 35–38. https://doi.org/10.1016/j.jns.2004.08.002.CrossRefPubMed

Guntert, T., Hanggi, P., Othman, A., Suriyanarayanan, S., Sonda, S., Zuellig, R. A., et al. (2016). 1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-d-aspartate receptor signaling. Neuropharmacology, 110(Pt A), 211–222. https://doi.org/10.1016/j.neuropharm.2016.03.033.CrossRefPubMed

Gupta, S. D., Gable, K., Alexaki, A., Chandris, P., Proia, R. L., Dunn, T. M., et al. (2015). Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. Journal of Biological Chemistry, 290(1), 90–98. https://doi.org/10.1074/jbc.M114.588236.CrossRefPubMed

Hornemann, T., Penno, A., Rütti, M. F., Ernst, D., Kivrak-Pfiffner, F., Rohrer, L., et al. (2009). The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. The Journal of Biological Chemistry, 284, 26322–26330. https://doi.org/10.1074/jbc.M109.023192.CrossRefPubMedPubMedCentral

Hornemann, T., Richard, S., Rütti, M. F., Wei, Y., von Eckardstein, A., Serine-palmitoyltransferase, M., et al. (2006). Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase. The Journal of Biological Chemistry, 281, 37275–37281. https://doi.org/10.1074/jbc.M608066200.CrossRefPubMed

Houlden, H., Blake, J., & Reily, M. M. (2004). Hereditary sensory neuropathies. Current Opinion in Neurology, 17(5), 569–577.CrossRefPubMed

Houlden, H., King, R., Blake, J., Groves, M., Love, S., Woodward, C., et al. (2006). Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain, 129, 411–425. https://doi.org/10.1093/brain/awh712.CrossRefPubMed

Klein, C. J., Wu, Y., Kruckeberg, K. E., Hebbring, S. J., Anderson, S. A., Cunningham, J. M., et al. (2005). SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies. Journal of Neurology, Neurosurgery and Psychiatry, 76(7), 1022–1024. https://doi.org/10.1136/jnnp.2004.050062.CrossRefPubMed

Laura, M., Murphy, S. M., Hornemann, T., Bode, H., Polke, J., Blake, J., et al. (2012). P42 Hereditary sensory neuropathy type 1: correlation of severity and plasma atypical deoxy-sphyngoid bases. Neuromuscular Disorders, 22, S18. https://doi.org/10.1016/S0960-8966(12)70050-0.CrossRef

Leipold, E., Liebmann, L., Korenke, G. C., Heinrich, T., Gieszelmann, S., Baets, J., et al. (2013). A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nature Genetics, 45(11), 1399–1404. https://doi.org/10.1038/ng.2767.CrossRefPubMed

Murphy, S. M., Ernst, D., Wei, Y., Laurà, M., Liu, Y.-T., Polke, J., et al. (2013). Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology, 80, 2106–2111. https://doi.org/10.1212/WNL.0b013e318295d789.CrossRefPubMedPubMedCentral

Penno, A., Reilly, M. M., Houlden, H., Laurá, M., Rentsch, K., Niederkofler, V., et al. (2010). Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. The Journal of Biological Chemistry, 285, 11178–11187. https://doi.org/10.1074/jbc.M109.092973.CrossRefPubMedPubMedCentral

Rotthier, A., Auer-Grumbach, M., Janssens, K., Baets, J., Penno, A., Almeida-Souza, L., et al. (2010). Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. American Journal of Human Genetics, 87(4), 513–522. https://doi.org/10.1016/j.ajhg.2010.09.010.CrossRefPubMedPubMedCentral

Rotthier, A., Penno, A., Rautenstrauss, B., Auer-Grumbach, M., Stettner, G. M., Asselbergh, B., et al. (2011). Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I. Human Mutation, 32(6), E2211–E2225. https://doi.org/10.1002/humu.21481.CrossRefPubMed

Suh, B. C., Hong, Y. B., Nakhro, K., Nam, S. H., Chung, K. W., & Choi, B.-O. (2014). Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. Molecular medicine Reports, 9, 481–486. https://doi.org/10.3892/mmr.2013.1808.CrossRefPubMed

Suriyanarayanan, S., Toppila, J., Auranen, M., Paetau, A., Shcherbii, M., Palin, E., et al. (2016). The variant p.(Arg183Trp) in SPTLC2 causes late-onset hereditary sensory neuropathy. NeuroMolecular Medicine, 18(1), 81–90. https://doi.org/10.1007/s12017-015-8379-1.CrossRefPubMed

Yard, B. A., Carter, L. G., Johnson, K. A., Overton, I. M., Dorward, M., Liu, H., et al. (2007). The structure of serine palmitoyltransferase; gateway to sphingolipid biosynthesis. Journal of Molecular Biology, 370(5), 870–886. https://doi.org/10.1016/j.jmb.2007.04.086.CrossRefPubMed

Title: A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C
Authors: Saranya Suriyanarayanan
Alaa Othman
Bianca Dräger
Anja Schirmacher
Peter Young
Lejla Mulahasanovic
Konstanze Hörtnagel
Saskia Biskup
Arnold von Eckardstein
Thorsten Hornemann
Museer A. Lone
Publication date: 01-06-2019
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 2/2019
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-019-08534-w

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A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C

Abstract

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