Myoclonus, Motor Deficits, Alterations in Emotional Responses and Monoamine Metabolism in ε-Sarcoglycan Deficient Mice

Yokoi, Fumiaki; Dang, Mai T.; Li, Jianyong; Li, Yuqing

doi:10.1093/jb/mvj138

Cited by 91 publications

(112 citation statements)

References 34 publications

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“…30,31 Moderate expression levels of the major brain-specific SGCE isoform in the striatum and lowest expression levels in the globus pallidus were found in all control subjects. We propose that observed striatal changes may be secondary owing to abnormal cerebellar signaling.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2010

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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

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Section: Discussionmentioning

confidence: 92%

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

et al. 2010

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“…We also reported the making of paternally inherited Sgce heterozygous KO mice, which also showed similar motor deficits at 6.57.5 months of age (31). In this study, we produced the single and double mutant mice and littermate control mice to evaluate their motor performance at 5.5 months of age and to determine whether the two mutations affect the age of onset of the motor deficits.…”

mentioning

confidence: 82%

“…We previously reported the making of Sgce KO mice lacking exon 4 and demonstrated that paternally inherited Sgce heterozygous KO mice did not express maternally inherited WT Sgce in the brain (27). The Sgce KO mice exhibited myoclonus, motor deficits, alterations in emotional responses and monoamine metabolism (31).…”

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confidence: 99%

Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Yokoi

Yang

et al. 2010

The Journal of Biochemistry

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“…Conversely, rodents may be more capable of compensating, and therefore loss of the protein may manifest as a lesser dysfunction compared to humans. Because the present genetic dystonia rodent models that have been generated are knock-ins, knockouts, or transgenics; the disrupted gene is present from conception [48,[57][58][59]. Embryonic alterations in gene expression may be able to compensate for the loss of gene in mice, but not in humans.…”

Section: Rodent Models Of Dystoniamentioning

confidence: 99%