Premium
Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I
Author(s) -
Rotthier Annelies,
Penno Anke,
Rautenstrauss Bernd,
AuerGrumbach Michaela,
Stettner Georg M.,
Asselbergh Bob,
Van Hoof Kim,
Sticht Heinrich,
Lévy Nicolas,
Timmerman Vincent,
Hornemann Thorsten,
Janssens Katrien
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21481
Subject(s) - biology , sphingolipid , hek 293 cells , in vitro , mutation , serine , gene knockdown , cancer research , microbiology and biotechnology , genetics , biochemistry , gene , enzyme
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. © 2011 Wiley‐Liss, Inc.