Autism in Several Members of a Family With Generalized Epilepsy With Febrile Seizures Plus

Dixon‐Salazar, Tracy; Keeler, Lesley C.; Trauner, Doris A.; Gleeson, Joseph G.

doi:10.1177/088307380401900806

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…Deletion of the CAM Lsamp in mice leads to heightened reactivity to novelty (Catania, et al 2008) and conditional deletion of L1-CAM in brain results in decreased anxiety-like behavior (Law, et al 2003). Epilepsy and neuropsychiatric disease have a bidirectional relationship of comorbidity (Dixon-Salazar, et al 2004; Gargus 2006; Jacoby and Thapar 2009; Pauli and Stefan 2009; Spence and Schneider 2009) and thus may share common genetic mechanisms. SCN1B -dependent regulation of neuronal pathfinding may be critical to abnormal brain development in both neurological and psychological disease.…”

Section: Discussionmentioning

confidence: 99%

Voltage-Gated Na⁺Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Patino¹,

Brackenbury²,

Bao³

et al. 2011

J. Neurosci.

100

143

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Scn1b null mice have a severe neurological and cardiac phenotype. Human mutations in SCN1B result in epilepsy and cardiac arrhythmia. SCN1B is expressed as two developmentally regulated splice variants, β1 and β1B, that are each expressed in brain and heart in rodents and humans. Here we studied the structure and function of β1B and investigated a novel human SCN1B epilepsy-related mutation (p.G257R) unique to β1B. We show that wild-type β1B is not a transmembrane protein, but a soluble protein expressed predominantly during embryonic development that promotes neurite outgrowth. Association of β1B with voltage-gated Na+ channels (VGSCs) Nav1.1 or Nav1.3 is not detectable by immunoprecipitation and β1B does not affect Nav1.3 cell surface expression as measured by [3H]-saxitoxin binding. However, β1B co-expression results in subtle alteration of Nav1.3 currents in transfected cells, suggesting that β1B may modulate Na+ current in brain. Similar to the previously characterized p.R125C mutation, p.G257R results in intracellular retention of β1B, generating a functional null allele. In contrast, two other SCN1B mutations associated with epilepsy, p.C121W and p.R85H, are expressed at the cell surface. We propose that β1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.

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Section: Discussionmentioning

confidence: 99%

Voltage-Gated Na⁺Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Patino¹,

Brackenbury²,

Bao³

et al. 2011

J. Neurosci.

100

143

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“…Autism spectrum disorders (ASDs) are comorbidities of DS (54) and some cases of GEFS+ (146). Thus, a promising avenue of investigation is ion channel expression in ASDs and other neuropsychiatric disease including mood disorders and psychiatric disorders, as many of these diseases share common genetic foundations.…”

Section: Channelopathies and Pathophysiology Of Vgsc β Subunitsmentioning

confidence: 99%

Sodium Channel β Subunits: Emerging Targets in Channelopathies

O’Malley

Isom

2015

Annu. Rev. Physiol.

218

255

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Voltage-gated sodium channels (VGSCs) are responsible for initiation and propagation of action potentials in excitable cells. VGSCs in mammalian brain are heterotrimeric complexes of α and β subunits. Originally called “auxiliary,” we now know that β subunit proteins are multifunctional signaling molecules that play roles in both excitable and non-excitable cell types, and with or without the pore-forming α subunit present. β subunits function in VGSC and potassium channel modulation, cell adhesion, and gene regulation, with particularly important roles in brain development. Mutations in the genes encoding β subunits are linked to a number of diseases, including epilepsy, sudden death syndromes like SUDEP and SIDS, and cardiac arrhythmia. While VGSC β subunit-specific drugs have not yet been developed, this protein family is an emerging therapeutic target.

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“…While the Brugada syndrome associated sodium channel beta subunit locus SCN1B is well recognized to carry alleles that cause the GEFS+ seizure phenotype (Wallace et al, 1998) and can cause ASD together with this syndrome (Dixon-Salazar et al, 2004), no mutations in these accessory sodium channel subunits have yet been clearly associated with the ASD phenotype independent of seizures.…”

Section: Sodium Channel Defects In Asdmentioning

confidence: 99%

Channelopathy pathogenesis in autism spectrum disorders

Schmunk¹,

Gargus²

2013

Front. Genet.

106

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Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

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Autism in Several Members of a Family With Generalized Epilepsy With Febrile Seizures Plus

Cited by 10 publications

References 25 publications

Voltage-Gated Na⁺Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Voltage-Gated Na⁺Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Sodium Channel β Subunits: Emerging Targets in Channelopathies

Channelopathy pathogenesis in autism spectrum disorders

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Autism in Several Members of a Family With Generalized Epilepsy With Febrile Seizures Plus

Cited by 10 publications

References 25 publications

Voltage-Gated Na+Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Voltage-Gated Na+Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Sodium Channel β Subunits: Emerging Targets in Channelopathies

Channelopathy pathogenesis in autism spectrum disorders

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Product

Resources

About

Voltage-Gated Na⁺Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

Voltage-Gated Na⁺Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy