Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I

Rotthier A, Penno A, Rautenstrauss B, Auer-Grumbach M, Stettner GM, Asselbergh B, Van Hoof K, Sticht H, Levy N, Timmerman V, Hornemann T, Janssens K (2011)

Publication Type: Journal article

Publication year: 2011

Journal

Human Mutation Wiley-Blackwell

Book Volume: 32

Pages Range: E2211-25

Journal Issue: 6

DOI: 10.1002/humu.21481

Abstract

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy leading to progressive distal sensory loss and severe ulcerations. Mutations in SPTLC1 and SPTLC2, encoding the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids, have been reported to cause HSAN-I. Here, we demonstrate that the SPTLC1 mutations p.S331F and p.A352V result in a reduction of SPT activity in vitro and are associated with increased levels of the deoxysphingoid bases 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine in patients' plasma samples. Stably expressing p.S331F-SPTLC1 HEK293T cell lines likewise show accumulation of deoxysphingoid bases, but this accumulation is not observed in HEK293T cells overexpressing p.A352V-SPTLC1. These results confirm that the increased formation of deoxysphingoid bases is a key feature for HSAN-I as it is associated with all pathogenic SPTLC1 and SPTLC2 mutations reported so far, but also warrant for caution in the interpretation of in vitro data.

Authors with CRIS profile

Heinrich Sticht Professur für Bioinformatik

Involved external institutions

University of Antwerp / Universiteit Antwerpen BE Belgium (BE) Universitätsspital Zürich (USZ) CH Switzerland (CH) Medizinisch Genetisches Zentrum (MGZ) / Medical Genetics Center DE Germany (DE) Georg-August-Universität Göttingen DE Germany (DE) Hôpital de la Timone FR France (FR)

How to cite

APA:

Rotthier, A., Penno, A., Rautenstrauss, B., Auer-Grumbach, M., Stettner, G.M., Asselbergh, B.,... Janssens, K. (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), E2211-25. https://dx.doi.org/10.1002/humu.21481

MLA:

Rotthier, Annelies, et al. "Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I." Human Mutation 32.6 (2011): E2211-25.

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