Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism.

An update of the enzymology and regulation of sphingomyelin metabolism

Hereditary sensory neuropathy type I (HSN1) is the most common hereditary disorder of peripheral sensory neurons. HSN1 is an autosomal dominant progressive degeneration of dorsal root ganglia and motor neurons with onset in the second or third decades. Initial symptoms are sensory loss in the feet followed by distal muscle wasting and weakness. Loss of pain sensation leads to chronic skin ulcers and distal amputations. The HSN1 locus has been mapped to chromosome 9q22.1-22.3 (refs. 3,4). Here we map the gene SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, to this locus. Mutation screening revealed 3 different missense mutations resulting 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 mutation to be located in exon 6 of SPTLC1 (V144D). All families showing definite or probable linkage to chromosome 9 had mutations in these two exons. These mutations are associated with increased de novo glucosyl ceramide synthesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death.

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

Sphingomyelin and derivatives as cellular signals.

Plant sphingolipids: structural diversity, biosynthesis, first genes and functions

Biosynthesis of sphingolipid bases. IV. The biosynthetic origin of sphingosine in Hansenula ciferri.

Biosynthesis of sphingosine and dihydrosphingosine by cell-free systems from Hansenula ciferri.

Biosynthesis of Sphingolipid Bases III. ISOLATION AND CHARACTERIZATION OF KETONIC INTERMEDIATES IN THE SYNTHESIS OF SPHINGOSINE AND DIHYDROSPHINGOSINE BY CELL-FREE EXTRACTS OF HANSENULA CIFERRI

Robert N. Brady

Papers

Biosynthesis of sphingolipid bases. IV. The biosynthetic origin of sphingosine in Hansenula ciferri.

Biosynthesis of sphingosine and dihydrosphingosine by cell-free systems from Hansenula ciferri.

Biosynthesis of Sphingolipid Bases III. ISOLATION AND CHARACTERIZATION OF KETONIC INTERMEDIATES IN THE SYNTHESIS OF SPHINGOSINE AND DIHYDROSPHINGOSINE BY CELL-FREE EXTRACTS OF HANSENULA CIFERRI