SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

Abstract

Myoclonus-dystonia (M-D) is a neurological movement disorder with involuntary jerky and dystonic movements as major symptoms. About 50% of M-D patients have a mutation in e-sarcoglycan (SGCE), a maternally imprinted gene that is widely expressed. As little is known about SGCE function, one can only speculate about the pathomechanisms of the exclusively neurological phenotype in M-D. We characterized different SGCE isoforms in the human brain using ultra-deep sequencing. We show that a major brain-specific isoform is differentially expressed in the human brain with a notably high expression in the cerebellum, namely in the Purkinje cells and neurons of the dentate nucleus. Its expression was low in the globus pallidus and moderate to low in caudate nucleus, putamen and substantia nigra. Electrophysiological studies in man suggest that myoclonic symptoms are of subcortical origin. [1][2][3] In general, dystonia is thought to arise from dysfunction of the basal ganglia. 4 About 50% of M-D patients who were classified as definite M-D carry a mutation in the widely expressed e-sarcoglycan (SGCE). [5][6][7] The genetic cause in the remaining patients is still unclear. A second locus has been reported in one large M-D family (DYT15, 18p11), but no gene has been identified yet. 8,9 SGCE is part of the sarcoglycan family that consists of N-glycosylated transmembrane proteins. Six different sarcoglycans have been identified so far (a-, b-, g-, d-, e-and z-), but little is known about the function of particular sarcoglycan members and their function in different tissues. 10 In muscles, sarcoglycans form a heterotetrameric complex that is constituent of the dystrophinassociated protein complex. This complex mediates the structural stability of the plasma membrane and interactions between the extracellular matrix and the cytoskeleton. 11 Mutations in other sarcoglycans, a-, b-, g-and d-sarcoglycan, lead to different forms of limb-girdle muscular dystrophy, characterized by progressive muscle weakness. 10 Little is known about composition and function of the dystrophin-associated protein complex in the brain. SGCE is highly homologous to a-sarcoglycan, 12 but no muscle

Alternative Approaches to Modeling Hereditary Dystonias

“…The generation of this model has revealed the importance of both the basal ganglia and cerebellum in DYT12. Specifically, it has demonstrated that sodium pump malfunction in the cerebellum is sufficient to induce dystonia, consistent with a growing body of literature supporting cerebellar involvement in dystonia [14,[99][100][101]. It has also been revealed that the interaction between these 2 regions is key in this disorder.…”

Expression of Dystrophins and the Dystrophin-Associated-Protein Complex by Pituicytes in Culture

“…In exemple, if the major band of b-DG corresponds to the 43 kDa isoform, a band at 65 kDa has been described by others [39]. Recently several isoform of e-SG have been found in the brain in addition to the major form [40]. Up to now few study focus on this aspect concerning the other sarcoglycans in the CNS, and we cannot rule out the fact that additional band seen by Western correspond to some additional isoforms.…”

Functional MRI study of response inhibition in myoclonus dystonia

“…Genetic studies using deep sequencing characterizing different SGCE isoforms in the human brain found low expression in the globus pallidus and moderate to low expression in caudate nucleus, putamen and substantia nigra. Hence, changes in the basal ganglia might not be causal, but rather an effect of the hyperkinetic movements (Ritz et al, 2011). This finding is corroborated by a DYT11 knock out mouse model that suggests that the loss of epsilon-sarcoglycan in the striatum contributes to motor deficits, but does not produce myoclonus (Yokoi et al, 2012).…”

“…Clinically, this suggestion is underlined by the alcohol responsiveness of the movement disorder, a hallmark of myoclonus-dystonia which is not shared by other hereditary dystonic syndromes, such as DYT1. Moreover, genetic studies using deep sequencing characterized different SGCE isoforms in the human brain with a major brain-specific isoform with high expression in the cerebellum, namely in the Purkinje cells and neurons of the dentate nucleus (Ritz et al, 2011). Furthermore, impaired saccadic adaptation in DYT11 mutation positive MD has been found, indicative of cerebellar dysfunction in MD (Hubsch et al, 2011).…”