<i>SCN4A</i>pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy

Bergareche, Alberto; Bednarz, Marcin; Sánchez, Elena; Krebs, Catharine E.; Ruíz‐Martínez, Javier; Riva, Patricia de la; Makarov, Vladimir; Gorostidi, Ana; Jurkat‐Rott, Karin; Martí-Massó, J.F.; Paisán-Ruı́z, Coro

doi:10.1093/hmg/ddv410

Cited by 28 publications

(33 citation statements)

References 53 publications

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“…The T-type calcium channel, Cav3.1, has been previously implicated in neuronal autorhythmicity [53, 54] and is thought to underlie tremors seen in Parkinson’s disease[55], enhanced physiological tremor, and in ET [56] and T-type calcium channel antagonists have been shown to reduce tremor in mouse models of ET [54, 57, 58]. The identification of CACNA1G in two ET families in the current study is consistent with recent reports of mutations in other ion channel genes in other ET families and the concept that the ETs are channelopathies [14, 15]. We previously reported the identification of a mutation in Kv9.2 ( KCNS2 ), that encodes an electrically silent voltage-gated K + channel α subunit, in a family with pure ET [15].…”

Section: Discussionsupporting

confidence: 90%

“…In two families with atypical ET, mutations were also identified in genes encoding voltage-gated sodium channel alpha subunits. In a family with epilepsy and ET, a disease-segregating mutation p.(Gly1537Ser) in the SCN4A gene was identified and functional analyses demonstrated more rapid channel kinetics and altered ion selectivity, which may contribute to the phenotype of tremor and epilepsy in this family [14]. In a four generation Chinese family, with early onset familial episodic pain and ET, a gain-of-function missense mutation p.(Arg225Cys) in SCN11A was identified [60].…”

Section: Discussionmentioning

confidence: 99%

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Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Odgerel

Hernández

Park

et al. 2018

Preprint

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Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative variant due to incomplete coverage of the entire coding region of the genome. Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n=40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare variant classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test and prioritization of candidate genes identified within families using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 (family D), which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). This work has identified candidate genes and pathways for ET that can now be prioritized for functional studies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Odgerel

Hernández

Park

et al. 2018

Preprint

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“…The protein encoded by SCN3A is a transmembrane sodium channel, which plays an important role in the neuronal function. Disruption of the functioning of such sodium channels can cause the emergence of a number of neurological diseases, including essential tremor (Bergareche et al, 2015 ), epilepsy (George, 2004 ; Helbig et al, 2008 ; Reid et al, 2009 ; Eijkelkamp et al, 2012 ; Oliva et al, 2012 ), multiple sclerosis (Waxman, 2006 ), painful neuropathy (Faber et al, 2012 ; Huang et al, 2014 ), myotonia (Jurkat-Rott et al, 2010 ; Stunnenberg et al, 2010 ) and paroxysmal myoplegia (Cannon, 2010 ). It is interesting to note that all three potentially pathogenetically significant variants have been identified by us for the first time and are located in the hydrophobic fifth segment of the SCHN3A protein that is directly responsible for ion transport.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson’s Disease

Shulskaya

Alieva

Vlasov

et al. 2018

Front. Aging Neurosci.

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Background: Parkinson’s disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated.Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas.Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database.Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant.Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.

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“…This suggests that the cellular environment is usually not able to invert the effect of a mutation from gain to loss of function phenotypes and reciprocally. Such comparison between Nav1.4 and Nav1.5 will probably draw more and more interest, to address the challenge of interpreting and understanding pathogenicity of rare SCN4A or SCN5A variants revealed by next-generation sequencing studies (Arnold et al, 2015 ; Bergareche et al, 2015 ; Coll et al, 2015 ).…”

Section: Comparison Of Missense Mutations Are There (Dys-) Functionamentioning

confidence: 99%

Physiological and Pathophysiological Insights of Nav1.4 and Nav1.5 Comparison

et al. 2016

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Mutations in Nav1.4 and Nav1.5 α-subunits have been associated with muscular and cardiac channelopathies, respectively. Despite intense research on the structure and function of these channels, a lot of information is still missing to delineate the various physiological and pathophysiological processes underlying their activity at the molecular level. Nav1.4 and Nav1.5 sequences are similar, suggesting structural and functional homologies between the two orthologous channels. This also suggests that any characteristics described for one channel subunit may shed light on the properties of the counterpart channel subunit. In this review article, after a brief clinical description of the muscular and cardiac channelopathies related to Nav1.4 and Nav1.5 mutations, respectively, we compare the knowledge accumulated in different aspects of the expression and function of Nav1.4 and Nav1.5 α-subunits: the regulation of the two encoding genes (SCN4A and SCN5A), the associated/regulatory proteins and at last, the functional effect of the same missense mutations detected in Nav1.4 and Nav1.5. First, it appears that more is known on Nav1.5 expression and accessory proteins. Because of the high homologies of Nav1.5 binding sites and equivalent Nav1.4 sites, Nav1.5-related results may guide future investigations on Nav1.4. Second, the analysis of the same missense mutations in Nav1.4 and Nav1.5 revealed intriguing similarities regarding their effects on membrane excitability and alteration in channel biophysics. We believe that such comparison may bring new cues to the physiopathology of cardiac and muscular diseases.

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SCN4Apore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy

Cited by 28 publications

References 53 publications

Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson’s Disease

Physiological and Pathophysiological Insights of Nav1.4 and Nav1.5 Comparison

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