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- Title
Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.
- Authors
Simpson, Michael A.; Cross, Harold; Proukakis, Christos; Priestman, David A.; Neville, David C. A.; Reinkensmeier, Gabriele; Heng Wang; Wiznitzer, Max; Gurtz, Kay; Verganelaki, Argyro; Pryde, Anna; Patton, Michael A.; Dwek, Raymond A; Butters, Terry D.; Platt, Frances M.; Crosby, Andrew H.
- 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 lactosylceramidea-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.
- Subjects
EPILEPSY; INFANTILE spasms; GENEALOGY; CHROMOSOMES; GANGLIOSIDES; LYSOSOMAL storage diseases
- Publication
Nature Genetics, 2004, Vol 36, Issue 11, p1225
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1460