title: Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome.
abstract: Loss-of-function mutations in SGCE, which encodes ε-sarcoglycan (ε-SG), cause myoclonus-dystonia syndrome (OMIM159900, DYT11). A "major" ε-SG protein derived from CCDS5637.1 (NM_003919.2) and a "brain-specific" protein, that includes sequence derived from alternative exon 11b (CCDS47642.1, NM_001099400.1), are reportedly localized in post- and pre-synaptic membrane fractions, respectively. Moreover, deficiency of the "brain-specific" isoform and other isoforms derived from exon 11b may be central to the pathogenesis of DYT11. However, no animal model supports this hypothesis. Gene-trapped ES cells (CMHD-GT_148G1-3, intron 9 of NM_011360) were used to generate a novel Sgce mouse model (C57BL/6J background) with markedly reduced expression of isoforms derived from exons 3' to exon 9 of NM_011360. Among those brain regions analyzed in adult (2month-old) wild-type (WT) mice, cerebellum showed the highest relative expression of isoforms incorporating exon 11b. Homozygotes (SgceGt(148G1)Cmhd/Gt(148G1)Cmhdor SgceGt/Gt) and paternal heterozygotes (Sgcem+/pGt, m-maternal, p-paternal) showed 60 to 70% reductions in expression of total Sgce. Although expression of the major (NM_011360) and brain-specific (NM_001130189) isoforms was markedly reduced, expression of short isoforms was preserved and relatively small amounts of chimeric ε-SG/β-galactosidase fusion protein was produced by the Sgce gene-trap locus. Immunoaffinity purification followed by mass spectrometry assessments of Sgcem+/pGtmouse brain using pan- or brain-specific ε-SG antibodies revealed significant reductions of ε-SG and other interacting sarcoglycans. Genome-wide gene-expression data using RNA derived from adult Sgcem+/pGtmouse cerebellum showed that the top up-regulated genes were involved in cell cycle, cellular development, cell death and survival, while the top down-regulated genes were associated with protein synthesis, cellular development, and cell death and survival. In comparison to WT littermates, Sgcem+/pGtmice exhibited "tiptoe" gait and stimulus-induced appendicular posturing between Postnatal Days 14 to 16. Abnormalities noted in older Sgcem+/pGtmice included reduced body weight, altered gait dynamics, and reduced open-field activity. Overt spontaneous or stimulus-sensitive myoclonus was not apparent on the C57BL/6J background or mixed C57BL/6J-BALB/c and C57BL/6J-129S2 backgrounds. Our data confirm that mouse Sgce is a maternally imprinted gene and suggests that short Sgce isoforms may compensate, in part, for deficiency of major and brain-specific Sgce isoforms.
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Satya R
authors.initials: SR
authors.lastname: Vemula
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Khan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cathays, Cardiff, CF24 4HQ, Great Britain, United Kingdom.
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Carlisle
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cathays, Cardiff, CF24 4HQ, Great Britain, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Waite
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cathays, Cardiff, CF24 4HQ, Great Britain, United Kingdom.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Blake
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dragatsis
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: mledoux@uthsc.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: LeDoux
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000378:metabolism*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005684:Gait / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D008297:Male; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D049031:Sarcoglycans / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D049031:Sarcoglycans
keywords: Dystonia; Gene trap; Myoclonus; Sarcoglycans; Sgce