Dataset Information

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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Publications

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

Similar Datasets

Project description:Myoclonus dystonia is a childhood-onset hyperkinetic movement disorder with a combined motor and psychiatric phenotype. It represents one of the few autosomal dominant inherited dystonic disorders and is caused by mutations in the ε-sarcoglycan (SGCE) gene. Work to date suggests that dystonia is caused by disruption of neuronal networks, principally basal ganglia-cerebello-thalamo-cortical circuits. Investigation of cortical involvement has primarily focused on disruption to interneuron inhibitory activity, rather than the excitatory activity of cortical pyramidal neurons. Here, we have sought to examine excitatory cortical glutamatergic activity using two approaches: the CRISPR/Cas9 editing of a human embryonic cell line, generating an SGCE compound heterozygous mutation, and three patient-derived induced pluripotent stem cell lines, each gene edited to generate matched wild-type SGCE control lines. Differentiation towards a cortical neuronal phenotype demonstrated no significant differences in either early- (PAX6, FOXG1) or late-stage (CTIP2, TBR1) neurodevelopmental markers. However, functional characterization using Ca2+ imaging and microelectrode array approaches identified an increase in network activity, while single-cell patch clamp studies found a greater propensity towards action potential generation with larger amplitudes and shorter half-widths associated with SGCE mutations. Bulk RNA sequencing analysis identified gene ontological enrichment for 'neuron projection development', 'synaptic signalling' and 'synaptic transmission'. Examination of dendritic morphology found SGCE mutations to be associated with a significantly higher number of branches and longer branch lengths, together with longer ion-channel dense axon initial segments, particularly towards the latter stages of differentiation (Days 80 and 100). Gene expression and protein quantification of key synaptic proteins (synaptophysin, synapsin and PSD95), AMPA and NMDA receptor subunits found no significant differences between the SGCE mutation and matched wild-type lines. By contrast, significant changes to synaptic adhesion molecule expression were identified, namely higher presynaptic neurexin-1 and lower postsynaptic neuroligin-4 levels in the SGCE mutation carrying lines. Our study demonstrates an increased intrinsic excitability of cortical glutamatergic neuronal cells in the context of SGCE mutations, coupled with a more complex neurite morphology and disruption to synaptic adhesion molecules. These changes potentially represent key components to the development of the hyperkinetic clinical phenotype observed in myoclonus dystonia, as well a central feature to the wider spectrum of dystonic disorders, potentially providing targets for future therapeutic development.