Nature Genetics
36, 1225 - 1229 (2004)
Published online: 24 October 2004; | doi:10.1038/ng1460
Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthaseMichael A Simpson1, Harold Cross2, Christos Proukakis1, David A Priestman3, David C A Neville3, Gabriele Reinkensmeier3, Heng Wang4, Max Wiznitzer5, Kay Gurtz6, Argyro Verganelaki1, Anna Pryde1, Michael A Patton1, Raymond A Dwek3, Terry D Butters3, Frances M Platt3
& Andrew H Crosby11
Department of Medical Genetics, St. George's Hospital Medical School, University of London, Cranmer Terrace, London SW17 0RE, UK. 2
Department of Ophthalmology, University of Arizona School of Medicine, 655 N. Alveron Way, Tucson, Arizona, USA. 3
Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. 4
Das Deutsch Clinic, Geauga County, Ohio, USA. 5
Rainbow Babies and Children's Hospital, Cleveland, USA. 6
Windows of Hope Genetic Studies, Kimmeridge Trail, Ohio 44065, USA.
Correspondence should be addressed to Andrew H Crosby acrosby@sghms.ac.ukWe 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  -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.
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