title: Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.
abstract: We identified an autosomal recessive infantile-onset symptomatic epilepsy syndrome associated with developmental stagnation and blindness. Assuming a founder effect in a large Old Order Amish pedigree, we carried out a genome-wide screen for linkage and identified a single region of homozygosity on chromosome 2p12-p11.2 spanning 5.1 cM (maximum lod score of 6.84). We sequenced genes in the region and identified a nonsense mutation in SIAT9, which is predicted to result in the premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). GM3 synthase is a member of the sialyltransferase family and catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide. Biochemical analysis of plasma glycosphingolipids confirmed that affected individuals lack GM3 synthase activity, as marked by a complete lack of GM3 ganglioside and its biosynthetic derivatives and an increase in lactosylceramide and its alternative derivatives. Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, this is the first report, to our knowledge, of a disruption of ganglioside biosynthesis associated with human disease.
authors.affiliation: Department of Medical Genetics, St. George's Hospital Medical School, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Harold
authors.initials: H
authors.lastname: Cross
authors.forename: Christos
authors.initials: C
authors.lastname: Proukakis
authors.forename: David A
authors.initials: DA
authors.lastname: Priestman
authors.forename: David C A
authors.initials: DC
authors.lastname: Neville
authors.forename: Gabriele
authors.initials: G
authors.lastname: Reinkensmeier
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.forename: Max
authors.initials: M
authors.lastname: Wiznitzer
authors.forename: Kay
authors.initials: K
authors.lastname: Gurtz
authors.forename: Argyro
authors.initials: A
authors.lastname: Verganelaki
authors.forename: Anna
authors.initials: A
authors.lastname: Pryde
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D001766:Blindness; D002889:Chromosomes, Human, Pair 2; D018389:Codon, Nonsense; D002658:Developmental Disabilities / Q000235:genetics; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005679:G(M3) Ganglioside / Q000097:blood; D005808:Genes, Recessive; D006028:Glycosphingolipids / Q000097:blood; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics*; D013577:Syndrome
chemical_list: D018389:Codon, Nonsense; D005679:G(M3) Ganglioside; D006028:Glycosphingolipids; D012799:Sialyltransferases; C021343:haematoside synthetase