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

Rotthier Annelies (1, 2) , Anke Penno (3, 4) , Bernd Rautenstrauss (5, 6) , Michalea Auer-Grumbach (7) , Georg M Stettner (8) , Bob Asselbergh (1) , Kim van Hoof (1) , Heinrich Sticht (9) , Nicolas Lévy (10, 11) , Vincent Timmerman (1) , Thorsten Hornemann (12, 13) , Katrien Janssens (1)

1 VIB Molecular Genetics
2 Laboratory of Neurogenetics
3 Clinical Chemistry
4 Competence Center for Systems Physiology and Metabolic Diseases
5 Medical Genetics Center
6 Friedrich-Baur Institute
7 Department of Internal Medicine, Devision of Endokrinology and Metabolism
8 Department of Pediatrics and Pediatric Neurology
9 Emil-Fischer-Zentrum, Institute of Biochemistry
10 Département de génétique médicale [Hôpital de la Timone - APHM]
11 Université de la Méditerranée - Aix-Marseille 2
12 Clinical Chemistry
13 Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP)

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.

Mots clés: Life Sciences

Rotthier Annelies, Anke Penno, Bernd Rautenstrauss, Michalea Auer-Grumbach, Georg M Stettner, et al.. Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I.. Human Mutation, 2011, 32 (6), ⟨10.1002/humu.21481⟩. ⟨hal-00616699⟩