SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells?

Kruth, Karina; Grisolano, Tierney M.; Ahern, Christopher A.; Williams, Ann E.

doi:10.1186/s13229-020-00330-9

Cited by 28 publications

(17 citation statements)

References 108 publications

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“…The largest gene discovery effort to date identified approximately 102 genes highly associated with ASD [58]. Emerging from these large-scale genetic studies are "channelopathies" or dysfunction of various ion channels as causative factors in ASD pathogenesis [59][60][61][62][63][64][65][66]. A substantial number of these genes are of the Na V , Ca V , and potassium channel families, as well as HCN channels [66].…”

Section: Impaired Dendritic Excitability and Synaptic Integration In Nddsmentioning

confidence: 99%

Dendritic Integration Dysfunction in Neurodevelopmental Disorders

Nelson¹,

Bender²

2021

Dev Neurosci

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Neurodevelopmental disorders (NDDs) that affect cognition, social interaction, and learning, including autism spectrum disorder (ASD) and intellectual disability (ID), have a strong genetic component. Our current understanding of risk genes highlights two main groups of dysfunction: those in genes that act as chromatin modifiers and those in genes that encode for proteins localized at or near synapses. Understanding how dysfunction in these genes contributes to phenotypes observed in ASD and ID remains a major question in neuroscience. In this review, we highlight emerging evidence suggesting that dysfunction in dendrites – regions of neurons that receive synaptic input – may be key to understanding features of neuronal processing affected in these disorders. Dendritic integration plays a fundamental role in sensory processing, cognition, and conscious perception, processes hypothesized to be impaired in NDDs. Many high-confidence ASD genes function within dendrites where they control synaptic integration and dendritic excitability. Further, increasing evidence demonstrates that several ASD/ID genes, including chromatin modifiers and transcription factors, regulate the expression or scaffolding of dendritic ion channels, receptors, and synaptic proteins. Therefore, we discuss how dysfunction of subsets of NDD-associated genes in dendrites leads to defects in dendritic integration and excitability and may be one core phenotype in ASD and ID.

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Section: Impaired Dendritic Excitability and Synaptic Integration In Nddsmentioning

confidence: 99%

Dendritic Integration Dysfunction in Neurodevelopmental Disorders

Nelson¹,

Bender²

2021

Dev Neurosci

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“…That these peptidomimetics bind to both FGF14 and Nav1.6 is desirable in that it affords multiple mechanisms by which they could modulate the PPI between FGF14 and Nav1.6. In the case of the inhibitor (12), its disruption of the PPI between FGF14 and Nav1.6 could be conferred via direct binding to the FGF14 interaction site on the C-terminal tail of Nav1.6 or via binding to FGF14 and causing the protein to undergo a conformational change that makes it inaccessible to its native interaction site on the C-terminal tail of Nav1.6. Similarly, for the potentiator of FGF14:Nav1.6 complex assembly (19), its modulatory effects on the PPI could be conferred by both binding to the C-terminal tail of Nav1.6 that makes the FGF14 interaction site increasingly accessible to the regulatory protein, or, conversely, by binding to FGF14 and causing it to undergo a conformational change that affords it with increased accessibility to its interaction site on the C-terminal tail of Nav1.6.…”

Section: Fgf14mentioning

confidence: 99%

“…Heretofore, it had been shown that addition of a N-terminal benzoyl substituent (19) to tetrapeptide analogs produced an efficacious potentiator of FGF14:Nav1.6 complex assembly, whereas truncation to a tripeptide (12) yielded an inhibitor of the complex s assembly. Additionally, both 12 and 19 demonstrated promising protein:ligand binding interactions.…”

Section: Electrophysiological Evaluation Of Compounds 12 and 19mentioning

confidence: 99%

“…Of the nine different pore-forming α-subunits that have been described (Nav1.1-1.9), the Nav1.1-1.3 and 1.6 isoforms are the primary Nav channels expressed in the central nervous system (CNS) [2]. Given their primacy in modulating neuronal excitability, it is unsurprising that aberrant activity of these isoforms has been implicated in the etiologies of numerous neurologic and neurodevelopmental disorders, including epilepsy [3][4][5][6], migraines [7][8][9], and autism [10][11][12]. Lending credence to the involvement of Nav channel aberrations in neuropsychiatric disorders, Nav channel blockers are also commonly used as adjunct therapies for the treatment of bipolar disorder [13,14], anxiety [15], and schizophrenia [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics

et al. 2020

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Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na+ (Nav) channels leads to neural circuitry aberrations that have been implicated in numerous channelopathies. One example of this pathophysiology is mediated by dysfunction of the PPI between Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). Thus, peptides derived from FGF14 might exert modulatory actions on the FGF14:Nav1.6 complex that are functionally relevant. The tetrapeptide Glu-Tyr-Tyr-Val (EYYV) mimics surface residues of FGF14 at the β8–β9 loop, a structural region previously implicated in its binding to Nav1.6. Here, peptidomimetics derived from EYYV (6) were designed, synthesized, and pharmacologically evaluated to develop probes with improved potency. Addition of hydrophobic protective groups to 6 and truncation to a tripeptide (12) produced a potent inhibitor of FGF14:Nav1.6 complex assembly. Conversely, addition of hydrophobic protective groups to 6 followed by addition of an N-terminal benzoyl substituent (19) produced a potentiator of FGF14:Nav1.6 complex assembly. Subsequent functional evaluation using whole-cell patch-clamp electrophysiology confirmed their inverse activities, with 12 and 19 reducing and increasing Nav1.6-mediated transient current densities, respectively. Overall, we have identified a negative and positive allosteric modulator of Nav1.6, both of which could serve as scaffolds for the development of target-selective neurotherapeutics.

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“…SCN2A has been reported as the gene with the strongest evidence for ASD-association based on exome analysis (12/4,109 cases) and second only to fragile X syndrome as a single-gene cause of ASD; recent reports suggest that SCN2A mutations may be associated with autism rates up to 50%. 8,[67][68][69] In these patients, symptoms are similar to those seen in more common forms of ASD, such as reduced social interaction and repetitive behaviors. Some patients also exhibit additional symptoms, such as intellectual disability and developmental delay, seizures, and symptoms of cerebellar dysfunction such as abnormal gait, clumsiness, and hypotonia.…”

Section: Intellectual Disability And/or Autism and Movement Disordersmentioning

confidence: 99%

SCN2A and Its Related Epileptic Phenotypes

Sullo

Pasquetti

Patanè

et al. 2021

Journal of Pediatric Neurology

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Epilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A-related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (usually within the first 10 years of life). Some patient may present with intellectual disability and/or autism or movement disorders and without epilepsy. The heterogeneity of the phenotypes associated to such genetic mutations does not always allow the clinician to address his suspect on this gene. For this reason, diagnosis is usually made after a multiple gene panel examination through next generation sequencing (NGS) or after whole exome sequencing (WES) or whole genome sequencing (WGS). Subsequently, confirmation by Sanger sequencing can be obtained. Mutations in SCN2A are inherited as an autosomal dominant trait. Most individuals diagnosed with SCN2A–benign familial neonatal-infantile seizures (BFNIS) have an affected parent; however, hypothetically, a child may present SCN2A-BNFNIS as the result of a de novo pathogenic variant. Almost all individuals with SCN2A and severe epileptic encephalopathies have a de novo pathogenic variant. SNC2A-related epilepsies have not shown a clear genotype–phenotype correlation; in some cases, a same variant may lead to different presentations even within the same family and this could be due to other genetic factors or to environmental causes. There is no “standardized” treatment for SCN2A-related epilepsy, as it varies in relation to the clinical presentation and the phenotype of the patient, according to its own gene mutation. Treatment is based mainly on antiepileptic drugs, which include classic wide-spectrum drugs, such as valproic acid, levetiracetam, and lamotrigine. However, specific agents, which act directly modulating the sodium channels activity (phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, and zonisamide), have shown positive result, as other sodium channel blockers (lidocaine and mexiletine) or even other drugs with different targets (phenobarbital).

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SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells?

Cited by 28 publications

References 108 publications

Dendritic Integration Dysfunction in Neurodevelopmental Disorders

Dendritic Integration Dysfunction in Neurodevelopmental Disorders

Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics

SCN2A and Its Related Epileptic Phenotypes

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