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

Simpson, Michael A.; Cross, Harold E.; Proukakis, Christos; Priestman, David A.; Neville, David C. A.; Reinkensmeier, Gabriele; Wang, Heng; Wiznitzer, Max; Gurtz, Kay; Verganelaki, Argyro; Pryde, Anna; Patton, Michael A.; Dwek, Raymond A.; Butters, Terry D.; Platt, Frances M.; Crosby, Andrew H.

doi:10.1038/ng1460

Cited by 360 publications

(322 citation statements)

References 21 publications

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“…in modulation of membrane-bound enzymes and ion-channels, cell-adhesion, neuritogenesis and membrane stability (Hakomori, 2003;Hashiramoto et al, 2006;Ledeen and Wu, 2006;Salazar et al, 2004;Sohn et al, 2006;Susuki et al, 2007;Wu et al, 2007;Yates and Rampersaud, 1998). Furthermore, anti-ganglioside autoimmunity and ganglioside turnover deficits cause neurological disorders (Ang et al, 2004;Maegawa et al, 2006;Simpson et al, 2004;Willison and Yuki, 2002).…”

Section: Introductionmentioning

confidence: 99%

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Zitman

Todorov

Verschuuren

et al. 2011

Neurobiology of Aging

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Gangliosides are sialylated glycosphingolipids that are present in high density on neuronal membranes, especially at synapses, where they are assumed to play functional or modulating roles. Mice lacking GM2/GD2-synthase express only the simple gangliosides GD3 and GM3 and develop progressive motor behaviour deficits upon ageing, apparently due to failing complex ganglioside-dependent maintenance and/or repair processes or, alternatively, toxic GM3/GD3 accumulation. We investigated the function of neuromuscular junctions (NMJs) of aged (>9 months-old) GM2/GD2-synthase null-mutant mice, because synaptic dysfunction might develop with age and could potentially contribute to the late-onset motor phenotype. In addition, we studied NMJs of old mice lacking GD3-synthase (expressing only O-and aseries gangliosides), which do not show an overt neurological phenotype but may develop subclinical synaptic deficits. Detailed electrophysiological analyses showed subtle changes in presynaptic neurotransmitter release. Acetylcholine release at 40 Hz nerve stimulation at aged GM2/GD2-synthase null-mutant NMJs ran down slightly more pronounced than at wild-type NMJs, and spontaneous acetylcholine release rate at GD3-synthase null-mutant NMJs was somewhat higher than at wild-type, selectively at 25 C bath temperature. Interestingly, we observed faster kinetics of postsynaptic electrophysiological responses at aged GD3-synthase null-mutant NMJs, not previously seen by us at NMJs of young GD3-synthase null-mutants or other types of (aged or young) ganglioside-deficient mice. These kinetic changes might reflect a change in postsynaptic acetylcholine receptor behaviour. Our data indicate that it is highly unlikely that transmission failure at NMJs contributes to the progressive motor defects of aged GM2/GD2-synthase null-mutants and that, despite some kinetic changes of synaptic signals, neuromuscular transmission remains successful in aged GD3-synthase null-mutant mice. Apparently, mutual redundancy of the different gangliosides in supporting presynaptic function, as observed previously by us in young mice, remains adequate upon ageing or, alternatively, gangliosides have only relatively little direct impact on neuromuscular synaptic function, even in aged mice. AbbreviationsACh, acetylcholine; AChR, acetylcholine receptor; EPP, endplate potential; GD3s-KO, α2,8-sialyltransferase knockout; GM2s-KO, β1,4-GalNAc-transferase knockout; MEPP, miniature endplate potential; NMJ, neuromuscular junction; WT, wild-type.Zitman et al., Synaptic function in aged ganglioside-deficient mice 3

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Section: Introductionmentioning

confidence: 99%

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Zitman

Todorov

Verschuuren

et al. 2011

Neurobiology of Aging

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“…They discovered that SIAT9, encoding GM3 synthase, contained a nonsense mutation that was predicted to cause premature termination of the protein product. Analysis of plasma glycosphingolipids in affected individuals confirmed the predicted block in the ganglioside biosynthesis pathway, as marked by substantial changes in the levels of several key gangliosides 3 .…”

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confidence: 65%

“…The discovery by Simpson et al 3 that a human epilepsy syndrome is caused by a defect in ganglioside synthesis is just the beginning of this story. Unraveling the mechanism underlying this disease will not only increase our understanding of epilepsies but also illuminate the crucial functions, now unequivocally established, of gangliosides in the brain.…”

Section: Possible Mechanismsmentioning

confidence: 99%

“…Now, on page 1225 of this issue, Simpson et al 3 describe a new gene underlying a severe early-onset symptomatic epilepsy syndrome. The gene, SIAT9, encodes a glycosyltransferase involved in the synthesis of gangliosides, glycosphingolipids containing sialic acid that are abundant in the plasma membrane of neurons.…”

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confidence: 99%

“…Simpson et al 3 began their work by searching for the genetic defect underlying an autosomal recessive epilepsy syndrome present in an Old Order Amish pedigree. The affected children in this pedigree develop seizure activity, including generalized tonic-clonic seizures, within the first year of life.…”

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confidence: 99%

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Gangliosides help stabilize the brain

Proia

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Emerging concepts of ganglioside metabolism

Sandhoff

2018

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Gangliosides (GGs) are sialic acid-containing glycosphingolipids (GSLs) and major membrane components enriched on cellular surfaces. Biosynthesis of mammalian GGs starts at the cytosolic leaflet of endoplasmic reticulum (ER) membranes with the formation of their hydrophobic ceramide anchors. After intracellular ceramide transfer to Golgi and trans-Golgi network (TGN) membranes, anabolism of GGs, as well as of other GSLs, is catalyzed by membrane-spanning glycosyltransferases (GTs) along the secretory pathway. Combined activity of only a few promiscuous GTs allows for the formation of cell-type-specific glycolipid patterns. Following an exocytotic vesicle flow to the cellular plasma membranes, GGs can be modified by metabolic reactions at or near the cellular surface. For degradation, GGs are endocytosed to reach late endosomes and lysosomes. Whereas membrane-spanning enzymes of the secretory pathway catalyze GSL and GG formation, a cooperation of soluble glycosidases, lipases and lipid-binding cofactors, namely the sphingolipid activator proteins (SAPs), act as the main players of GG and GSL catabolism at intralysosomal luminal vesicles (ILVs).

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

Cited by 360 publications

References 21 publications

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Gangliosides help stabilize the brain

Emerging concepts of ganglioside metabolism

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