<i>SYNE1</i>Mutations in Autosomal Recessive Cerebellar Ataxia

Noreau, Anne; Bourassa, Cynthia V.; Szuto, Anna; Levert, Annie; Dobrzeniecka, Sylvia; Gauthier, Julie; Forlani, Sylvie; Dürr, Alexandra; Anheim, Mathieu; Stevanin, Giovanni; Brice, Alexis; Bouchard, Jean‐Pierre; Dupré, Nicolas; Rouleau, Guy A.

doi:10.1001/jamaneurol.2013.3268

Cited by 45 publications

(51 citation statements)

References 5 publications

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“…10 Because of the large size of this gene with 146 exons in the canonical transcript (ENST00000423061; Ensembl database; http://www.ensembl.org/), next-generation sequencing is the only cost-effective means for routine clinical screening. 10 Previously only reported in the French-Canadian population, more widespread sequencing efforts have identified additional cases from France (1 case), Brazil (1 case), and Japan (3 cases), 32–34 consistent with the observation of multiple cases in this cohort and suggesting this to be a worldwide disorder with higher prevalence than previously known.…”

Section: Discussionsupporting

confidence: 84%

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

et al. 2014

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he diagnostic evaluation of a patient with chronic progressive cerebellar ataxia is clinically challenging. Cerebellar ataxia is associated with a heterogeneous array of neurologic conditions spanning common acquired etiologies to rare genetic disorders present only in single families. [1][2][3][4][5] Currently, more than 60 distinct neurogenetic conditions are known to cause primary cerebellar ataxia. In most cases, it is difficult to differentiate these disorders owing to phenotype variability within a disorder and overlap between disorders. [1][2][3][4][5] Further complicating matters, there are nearly 300 additional genetic conditions that can include cerebellar ataxia as a clinical finding. 6 Many patients present to clinicians with lateonset symptoms and no reported family history 7 and, in the absence of other identifying etiologies, the role of genetic disease in this population is not well understood. 1,3,5 The availability of next-generation clinical exome sequencing (CES) has made it possible to perform genomewide genetic evaluations for patients as part of a detailed clinical workup. 8,9 This is a potentially useful addition to the physician's armamentarium because, given the number of rare genes related to ataxia, overuse of low-yield single-gene and genetic panel testing represents a significant cost to patient health care. 7,10 The anticipated widespread benefits of CES have already prompted recommendations for its inclusion as part of routine clinical algorithms. 4,5,9,11,12 Although CES is much less expensive than sequentially examining mul-IMPORTANCE Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.OBJECTIVE To investigate the contribution of genetic disease in a population of patients with predominantly adult-and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTSWe examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURESNext-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTSWe identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELE...

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Section: Discussionsupporting

confidence: 84%

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

et al. 2014

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“…In light of the role of rootlets in the maintenance of ciliary functions [33–35], this new biological paradigm for Nesprin1 at ciliary rootlets is of significant clinical significance. 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].…”

Section: Resultsmentioning

confidence: 99%

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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“…Recessive mutations in SYNE1 were identified as a cause of cerebellar ataxia in 2007 20 and consequently designated ARCA1 and SCAR8. 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).…”

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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SYNE1Mutations in Autosomal Recessive Cerebellar Ataxia

Cited by 45 publications

References 5 publications

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

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

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