title: A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.
abstract: Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells--a SPTLC1 deficient CHO cell line--could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP.
authors.affiliation: Department for Clinical Chemistry, University Hospital Zurich, Raemistrasse 100, 8051, Zürich, Switzerland. thorsten.hornemann@usz.ch
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.forename: Anke
authors.initials: A
authors.lastname: Penno
authors.forename: Stephane
authors.initials: S
authors.lastname: Richard
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Fleur S
authors.initials: FS
authors.lastname: van Dijk
authors.forename: Annelies
authors.initials: A
authors.lastname: Rotthier
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
mesh_terms: D000818:Animals; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051102:Serine C-Palmitoyltransferase / Q000235:genetics*
chemical_list: C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase