Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain basesubunit-1, cause hereditary sensory neuropathy type I

Hereditary sensory neuropathy type I (HSN1) is the most common hereditary d isorder of peripheral sensory neurons. HSN1 is an autosomal dominant progre ssive degeneration of dorsal root ganglia and motor neurons with onset in t he second or third decades. Initial symptoms are sensory loss in the feet f ollowed by distal muscle wasting and weakness. Loss of pain sensation leads to chronic: skin ulcers and distal amputations(1,2). The HSN1 locus has be en mapped to chromosome 9q22.1-22.3 (refs. 3,4). Here we map the gene SPTLC 1, encoding serine palmitoyltransferase. long chain base subunit-l. to this locus. Mutation screening revealed 3 different missense mutations resultin g in changes to 2 amino acids in all affected members of 11 HSN1 families. We found two mutations to be located in exon 5 (C133Y and C133W) and one mu tation to be located in exon 6 of SPTLC1 (V144D). All families showing defi nite or probable linkage to chromosome 9 had mutations in these two exons. These mutations are associated with increased de novo glucosyl ceramide syn thesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis(5,6) and is associated with massive cell death during neural tube closure(7), raising the possibility that neur al degeneration in HSN1 is due to ceramide-induced apoptotic cell death.