Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Eichler, Florian; Hornemann, Thorsten; McCampbell, Alex; Kuljis, Dika; Penno, Anke; Vardeh, Daniel; Tamrazian, Eric; Garofalo, Kevin; Lee, Ho‐Joon; Kini, Lohit; Selig, Martin K.; Frosch, Matthew P.; Gable, Ken; Eckardstein, Arnold von; Woolf, Clifford J.; Guan, Guiman; Harmon, Jeffrey M.; Dunn, Teresa M.; Brown, Robert H.

doi:10.1523/jneurosci.2536-09.2009

Cited by 90 publications

(105 citation statements)

References 18 publications

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“…Elevated DSB levels were also found in plasma of mice that are transgenic for the SPTLC1C133W mutant as reported recently (25). Interestingly, double transgenic mice, which concomitantly overexpress the C133W mutant together with wildtype SPTLC1, do not develop neurological symptoms (25).…”

Section: Discussionsupporting

confidence: 72%

“…However, DSB levels in the double transgenic mice are still higher than in wild-type, SPTLC1 wild type-overexpressing mice, or heterozygous SPTLC1 ϩ/Ϫ knock-out mice, suggesting that DSBs can be tolerated up to a certain threshold level. Tissue analysis revealed the presence of highly elevated DSB levels in the sciatic nerves of the C133W mice but not of wildtype mice (25). No differences in the DSB levels were seen in brain tissue of C133W and wild-type mice.…”

Section: Discussionmentioning

confidence: 84%

“…Interestingly, double transgenic mice, which concomitantly overexpress the C133W mutant together with wildtype SPTLC1, do not develop neurological symptoms (25). This correlates with significantly lower DSB plasma levels in these mice.…”

Section: Discussionmentioning

confidence: 95%

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Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids

Penno

Reilly

Houlden

et al. 2010

Journal of Biological Chemistry

340

408

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HSAN1 is an inherited neuropathy found to be associated with several missense mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Here we show that the HSAN1 mutations induce a shift in the substrate specificity of SPT, which leads to the formation of the two atypical deoxysphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C 1 hydroxyl group of sphinganine and can therefore neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell, as demonstrated in HEK293 cells overexpressing mutant SPTLC1 and lymphoblasts of HSAN1 patients. Elevated DSB levels were also found in the plasma of HSAN1 patients and confirmed in three groups of HSAN1 patients with different SPTLC1mutations. The DSBs show pronounced neurotoxic effects on neurite formation in cultured sensory neurons. The neurotoxicity co-occurs with a disturbed neurofilament structure in neurites when cultured in the presence of DSBs. Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 84%

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Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids

Penno

Reilly

Houlden

et al. 2010

Journal of Biological Chemistry

340

408

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“…Previously, we showed that the increased formation of dSLs is the pathological cause of the inherited neuropathy HSAN1 [15,31]. Clinically, HSAN1 closely resembles the diabetic peripheral neuropathy (DPN) that occurs in about 60% of diabetic patients.…”

Section: Discussionmentioning

confidence: 96%

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

et al. 2011

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Aims/hypothesis Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C 12 to C 18 ) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes.Methods We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n=25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. Results Deoxysphingolipids (dSLs) were significantly elevated (p ¼ 5 Â 10 À6 ) in patients with the metabolic syndrome (0.11±0.04 μmol/l) compared with controls (0.06±0.02 μmol/l) but did not differ between the metabolic A. Othman and M. F. Rütti contributed equally to this study. Diabetologia (2012) 55:421-431 DOI 10.1007/s00125-011-2384 syndrome and diabetes groups. Levels of C 16 -sphingosinebased sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p=0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. Conclusions/interpretation We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.

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“…13 The 1-deoxySLs were shown to be neurotoxic, blocking neurite formation in cultured neurons. 11 Herein, we report a novel HSANI mutation in SPTLC2 associated with elevated plasma 1-deoxySLs.…”

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confidence: 99%

Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2

Murphy

Ernst

et al. 2013

Neurology

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Objective: To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation. Methods:We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays.Results: A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). Biochemically, the A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity. Conclusion:This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing HSANI. Hereditary sensory and autonomic neuropathy type 1 (HSANI) is an autosomal dominant (AD) sensory neuropathy complicated by ulcerations and amputations, with variable autonomic and motor involvement.1 To date, mutations in 5 genes have been reported to cause AD HSANI. 2-7Mutations in the enzyme serine palmitoyltransferase (SPT) cause HSANI. 2,3 SPT is a heteromeric enzyme composed of 3 subunits (SPTLC1-3) located at the outer membrane of the endoplasmic reticulum. 8,9 It catalyzes the first and rate-limiting step in de novo sphingolipid synthesis: the condensation of L-serine and palmitoyl-coenzyme A. Mutations in SPTLC1 account for 12% of patients with HSAN. 10 More recently, mutations in SPTLC2 were found to cause HSANI with a similar phenotype.4 SPTLC1 and SPTLC2 mutations generally cause a shift in the substrate specificity of SPT leading to the alternative use of L-alanine and L-glycine over its canonical substrate L-serine. 11,12 This forms an atypical category of 1-deoxysphingolipids (1-deoxySLs) lacking the C1 hydroxyl group, which impedes their conversion into complex sphingolipids but also their canonical degradation. Elevated 1-deoxySLs were found in the plasma and lymphoblasts of patients with HSANI 11 and plasma and tissues of transgenic HSANI *Joint first authors. These authors contributed equally to this work. ‡Joint senior authors.From the

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Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Cited by 90 publications

References 18 publications

Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids

Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2

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