title: Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I.
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: Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors: Annelies
authors: A
authors: Rotthier
authors: Anke
authors: A
authors: Penno
authors: Bernd
authors: B
authors: Rautenstrauss
authors: Michaela
authors: M
authors: Auer-Grumbach
authors: Georg M
authors: GM
authors: Stettner
authors: Bob
authors: B
authors: Asselbergh
authors: Kim
authors: K
authors: Van Hoof
authors: Heinrich
authors: H
authors: Sticht
authors: Nicolas
authors: N
authors: Lévy
authors: Vincent
authors: V
authors: Timmerman
authors: Thorsten
authors: T
authors: Hornemann
authors: Katrien
authors: K
authors: Janssens