期刊
HUMAN MUTATION
卷 32, 期 6, 页码 E2211-E2225出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.21481
关键词
HSAN-I; SPTLC1; serine palmitoyltransferase; 1-deoxy-sphinganine
资金
- University of Antwerp
- Fund for Scientific Research (FWO-Flanders)
- Medical Foundation Queen Elisabeth (GSKE)
- 'Association Belge contre les Maladies Neuromusculaires' (ABMM)
- Belgian Federal Science Policy Office (BELSPO) [P6/43]
- Institute for Science and Technology (IWT)
- EMBO
- BELSPO
- German Society for Clinical Chemistry and Laboratory Medicine (DGKL)
- Gebert Ruf Foundation
- European Commission [LSHM-CT-2006-037631]
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. (C) 2011 Wiley-Liss, Inc.
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