Multisystemic<i>SYNE1</i>ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum

Mademan, Inès; Harmuth, Florian; Giordano, Ilaria; Timmann, Dagmar; Magri, Stefania; Deconinck, Tine; Claaßen, Jens; Jokisch, Daniel; Genç, Gençer; Bella, Daniela Di; Romito, Silvia; Schüle, Rebecca; Züchner, Stephan; Taroni, Franco; Klockgether, Thomas; Schöls, Lüdger; Jonghe, Peter De; Bauer, Péter; Baets, Jonathan; Synofzik, Matthis

doi:10.1093/brain/aww115

Cited by 44 publications

(45 citation statements)

References 11 publications

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“…Indeed, biallelic truncations of SYNE1 underlie autosomal recessive cerebellar ataxia Type I (ARCA1), a progressive form of pure cerebellar ataxia that consists of limb and gait ataxia, dysarthria and severe cerebellar atrophy [13, 36, 37]. More recent studies have emphasized that these cerebellar pathologies are most often accompanied by variable combinations of multisystemic pathologies that include upper and lower motor neuron disease, muscle atrophy and spasticity, kyphoscoliosis, respiratory distress and neurocognitive disorders [14, 15, 38–40]. The molecular pathogenesis of these mutations is currently unknown but our results suggest that at least a subset of these pathologies may be linked to a loss of function of ciliary Nesprin1.…”

Section: Resultsmentioning

confidence: 99%

“…The molecular pathogenesis of these mutations is currently unknown but our results suggest that at least a subset of these pathologies may be linked to a loss of function of ciliary Nesprin1. To that respect, several pathologies associated with SYNE1 mutations include respiratory distress, kyphoscoliosis or mental retardation [14, 15], a set of phenotypes commonly associated with human ciliopathies [41]. The docking of rootletin filaments by SUN2/Nesprin1 LINC complexes has many biological implications.…”

Section: Resultsmentioning

confidence: 99%

“…In agreement with the association of Nesprin1α with photoreceptor ciliary rootlets and the functional interaction between rootletin and Nesprin1 in fibroblasts, we demonstrate that multiple isoforms of Nesprin1 are integral components of ciliary rootlets of multiciliated ependymal and tracheal cells. Together, these data provide a novel functional paradigm for Nesprin1 at ciliary rootlets and suggest that the wide spectrum of human pathologies linked to truncating mutations of SYNE1 [13–15] may in part originate from ciliary defects. …”

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confidence: 89%

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Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

et al. 2017

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SUMMARY SYNE1 (Synaptic nuclear envelope 1) encodes multiple isoforms of Nesprin1 (Nuclear Envelope Spectrin 1) that associate with the nuclear envelope (NE) through a C-terminal KASH (Klarsicht/Anc1/Syne homology) domain (Figure 1A) [1–4]. This domain interacts directly with the SUN (Sad1/Unc84) domain of Sun proteins [5–7], a family of transmembrane proteins of the inner nuclear membrane (INM) [8, 9], to form the so-called LINC complexes (Linkers of the Nucleoskeleton and the Cytoskeleton) that span the whole NE and mediate nuclear positioning [10–12]. In a stark departure from this classical depiction of Nesprin1 in the context of the NE, we report that rootletin recruits Nesprin1α at the ciliary rootlets of photoreceptors and identified asymmetric NE aggregates of Nesprin1α and Sun2 that dock filaments of rootletin at the nuclear surface. In NIH3t3 cells, we show that recombinant rootletin filaments also dock to the NE through the specific recruitment of a ~600 kDa endogenous isoform of Nesprin1 (Nes1600kDa) and of Sun2. In agreement with the association of Nesprin1α with photoreceptor ciliary rootlets and the functional interaction between rootletin and Nesprin1 in fibroblasts, we demonstrate that multiple isoforms of Nesprin1 are integral components of ciliary rootlets of multiciliated ependymal and tracheal cells. Together, these data provide a novel functional paradigm for Nesprin1 at ciliary rootlets and suggest that the wide spectrum of human pathologies linked to truncating mutations of SYNE1 [13–15] may in part originate from ciliary defects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 89%

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Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

et al. 2017

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“…For almost a decade mutations in SYNE1 were thought to cause a slowly progressive, largely pure cerebellar ataxia, 21,22 before it was realized in 2016 that they are in fact causative for a broad pleiotropic phenotypic spectrum, with corticospinal tract damage and even predominant complicated HSP presentations among the most frequent features. 23,24 Recessive mutations in PLA2G6 were found in 2006 to cause, among others, a childhood-onset ataxia cluster (termed infantile neuroaxonal dystrophy). 25 Although concomitant corticospinal tract features have already been described in several reports in recent years, it was not until recently that complicated HSP has been acknowledged as one of the main phenotypic presentations of PLA2G6 (Ozes et al, submitted).…”

Section: Discovering the Phenotypic And Genetic Spectrum From The Extmentioning

confidence: 99%

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

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Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.

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“…As for the ALS consensus novel predictions, missense variants in SYNE1 have been reported to be associated with a multisystemic neurological phenotypic spectrum that includes amyotrophic lateral sclerosis 42,43,44 . ALDH5A1 is significantly down-regulated in the spinal cord of an ALS murine model 45 while ABCA1 is among the altered genes in frontal cortex of ALS samples 46 .…”

Section: Application Of Mantis-ml Predictions To Triage Results From mentioning

confidence: 99%

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

Vitsios

Petrovski

2019

Preprint

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Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses that result in candidate lists of genes. Often these analyses highlight several gene signals that might contribute to pathogenesis but are insufficiently powered to reach experiment-wide significance. This often triggers a process of laborious evaluation of highly-ranked genes through manual inspection of various public knowledge resources to triage those considered sufficiently interesting for deeper investigation. Here, we introduce a novel multi-dimensional, multi-step machine learning framework to objectively and more holistically assess biological relevance of genes to disease studies, by relying on a plethora of gene-associated annotations. We developed mantis-ml to serve as an automated machine learning (AutoML) framework, following a stochastic semisupervised learning approach to rank known and novel disease-associated genes through iterative training and prediction sessions of random balanced datasets across the protein-coding exome (n=18,626 genes). We applied this framework on a range of disease-specific areas and as a generic disease likelihood estimator, achieving an average Area Under Curve (AUC) prediction performance of 0.85. Critically, to demonstrate applied utility on exome-wide association studies, we overlapped mantis-ml disease-specific predictions with data from published cohort-level association studies. We retrieved statistically significant enrichment of high mantis-ml predictions among the top-ranked genes from hypothesis-free cohort-level statistics (p<0.05), suggesting the capture of true prioritisation signals. We believe that mantis-ml is a novel easy-to-use tool to support objectively triaging gene discovery and overall enhancing our understanding of complex genotype-phenotype associations.

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MultisystemicSYNE1ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum

Cited by 44 publications

References 11 publications

Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

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