Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase (original) (raw)

Nature Genetics volume 36, pages 1225–1229 (2004)Cite this article

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 α-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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Acknowledgements

We thank the Amish families for their help and support and the Das Deutsch Centre for facilitating contact with the affected individuals. This work was supported by The Birth Defects Foundation UK, The Wellcome Trust and Research to Prevent Blindness.

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Authors and Affiliations

  1. Department of Medical Genetics, St. George's Hospital Medical School, University of London, Cranmer Terrace, London, SW17 0RE, UK
    Michael A Simpson, Christos Proukakis, Argyro Verganelaki, Anna Pryde, Michael A Patton & Andrew H Crosby
  2. Department of Ophthalmology, University of Arizona School of Medicine, 655 N. Alveron Way, Tucson, Arizona, USA
    Harold Cross
  3. Department of Biochemistry, Glycobiology Institute, University of Oxford, Oxford, OX1 3QU, UK
    David A Priestman, David C A Neville, Gabriele Reinkensmeier, Raymond A Dwek, Terry D Butters & Frances M Platt
  4. Das Deutsch Clinic, Geauga County, Ohio, USA
    Heng Wang
  5. Rainbow Babies and Children's Hospital, Cleveland, USA
    Max Wiznitzer
  6. Windows of Hope Genetic Studies, Kimmeridge Trail, 44065, Ohio, USA
    Kay Gurtz

Authors

  1. Michael A Simpson
  2. Harold Cross
  3. Christos Proukakis
  4. David A Priestman
  5. David C A Neville
  6. Gabriele Reinkensmeier
  7. Heng Wang
  8. Max Wiznitzer
  9. Kay Gurtz
  10. Argyro Verganelaki
  11. Anna Pryde
  12. Michael A Patton
  13. Raymond A Dwek
  14. Terry D Butters
  15. Frances M Platt
  16. Andrew H Crosby

Corresponding author

Correspondence toAndrew H Crosby.

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The authors declare no competing financial interests.

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Simpson, M., Cross, H., Proukakis, C. et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.Nat Genet 36, 1225–1229 (2004). https://doi.org/10.1038/ng1460

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