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A Novel SGCE Nonsense Variant Associated With Marked Intrafamilial Variability in a Turkish Family With Myoclonus-Dystonia.

ABSTRACT: Background:Myoclonus-Dystonia syndrome (M-D) is an autosomal-dominant movement disorder related to SGCE gene pathogenic variants. Although there can be observed variability in clinical findings, here we describe intrafamilial variability in a Turkish family with a novel nonsense SGCE pathogenic variant. Methods:A family with variable clinical symptoms resembling M-D were referred to our clinic. After preliminary diagnosis, patients were tested for mutations in the SGCE gene by Sanger sequencing. Results:Novel pathogenic heterozygous nonsense mutation in exon 3, c.272T>G; p.Leu91* (NM_003919.2) were observed in affected family members. Conclusion:Intrafamilial clinical variability, despite the same pathogenic variant described in this work, suggests that there are regulatory factors, epigenetic or environmental modifiers, which are the subject of a matter for future studies.

SUBMITTER: Gultekin M

PROVIDER: S-EPMC6660223 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A Novel <i>SGCE</i> Nonsense Variant Associated With Marked Intrafamilial Variability in a Turkish Family With Myoclonus-Dystonia.

Gultekin Murat M Prakash Neha N Ganos Christos C Mirza Meral M Bayramov Ruslan R Bhatia Kailash P KP Mencacci Niccolò E NE

Movement disorders clinical practice 20190717 6

<h4>Background</h4>Myoclonus-Dystonia syndrome (M-D) is an autosomal-dominant movement disorder related to <i>SGCE</i> gene pathogenic variants. Although there can be observed variability in clinical findings, here we describe intrafamilial variability in a Turkish family with a novel nonsense <i>SGCE</i> pathogenic variant.<h4>Methods</h4>A family with variable clinical symptoms resembling M-D were referred to our clinic. After preliminary diagnosis, patients were tested for mutations in the <i ...[more]

PMID: 31392249

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Project description:Loss-of-function mutations in SGCE, which encodes ?-sarcoglycan (?-SG), cause myoclonus-dystonia syndrome (OMIM159900, DYT11). A "major" ?-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)Cmhd or 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 ?-SG/?-galactosidase fusion protein was produced by the Sgce gene-trap locus. Immunoaffinity purification followed by mass spectrometry assessments of Sgcem+/pGt mouse brain using pan- or brain-specific ?-SG antibodies revealed significant reductions of ?-SG and other interacting sarcoglycans. Genome-wide gene-expression data using RNA derived from adult Sgcem+/pGt mouse 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+/pGt mice exhibited "tiptoe" gait and stimulus-induced appendicular posturing between Postnatal Days 14 to 16. Abnormalities noted in older Sgcem+/pGt mice 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.

Dataset Information

A Novel SGCE Nonsense Variant Associated With Marked Intrafamilial Variability in a Turkish Family With Myoclonus-Dystonia.

Publications

A Novel <i>SGCE</i> Nonsense Variant Associated With Marked Intrafamilial Variability in a Turkish Family With Myoclonus-Dystonia.

Similar Datasets

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