Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy

Sugawara, Takashi; Mazaki-Miyazaki, Emi; Fukushima, Katsuyuki; Shimomura, Jiro; Fujiwara, Tateki; Hamano, Shin‐ichiro; Inoue, Yushi; Yamakawa, Kazuhiro

doi:10.1212/wnl.58.7.1122

Cited by 222 publications

(138 citation statements)

References 9 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…Severe myoclonic epilepsy of infancy occurs in heterozygotes with a nonsense mutation in the Nav1.1 neuronal sodium channel. 20 A loss-of-function mutation may also result from a dominant-negative effect on the multimeric composition of the channel complex. For example, missense mutations of the Kir2.1 K channel in Anderson-Tawil syndrome …”

Section: Ion Channel Defects In Channelopathies Of Brain and Musclementioning

confidence: 99%

Physiologic Principles Underlying Ion Channelopathies

Cannon

2007

Neurotherapeutics

View full text Add to dashboard Cite

Summary:The ion channelopathies are a diverse array of human disorders caused by mutations in genes coding for ion channels. More than 40 different channelopathies have been identified, with representative disorders from every major class of ion channel and affecting all electrically excitable tissues: brain, peripheral nerve, skeletal muscle, smooth muscle, and heart. This review provides an overview of ion channel classification, structure, and function as a framework for understanding which ion channel properties are altered by disease-associated mutations and how these changes disrupt cellular excitability for channelopathies affecting skeletal muscle and the CNS.

show abstract

Section: Ion Channel Defects In Channelopathies Of Brain and Musclementioning

confidence: 99%

Physiologic Principles Underlying Ion Channelopathies

Cannon

2007

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…Subsequent reports of SCN1A mutations have further implicated SCN1A dysfunction in GEFSϩ Sugawara et al, 2001a;Wallace et al, 2001b). Moreover, SCN1A mutations were also described in patients with severe myoclonic epilepsy in infancy (SMEI; Claes et al, 2001;Sugawara et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

Kamiya¹,

Kaneda²,

Sugawara³

et al. 2004

J. Neurosci.

186

146

View full text Add to dashboard Cite

Mutations, exclusively missense, of voltage-gated sodium channel ␣ subunit type 1 (SCN1A) and type 2 (SCN2A) genes were reported in patients with idiopathic epilepsy: generalized epilepsy with febrile seizures plus. Nonsense and frameshift mutations of SCN1A, by contrast, were identified in intractable epilepsy: severe myoclonic epilepsy in infancy (SMEI). Here we describe a first nonsense mutation of SCN2A in a patient with intractable epilepsy and severe mental decline. The phenotype is similar to SMEI but distinct because of partial epilepsy, delayed onset (1 year 7 months), and absence of temperature sensitivity. A mutational analysis revealed that the patient had a heterozygous de novo nonsense mutation R102X of SCN2A. Patch-clamp analysis of Na v 1.2 wild-type channels and the R102X mutant protein coexpressed in human embryonic kidney 293 cells showed that the truncated mutant protein shifted the voltage dependence of inactivation of wild-type channels in the hyperpolarizing direction. Analysis of the subcellular localization of R102X truncated protein suggested that its dominant negative effect could arise from direct or indirect cytoskeletal interactions of the mutant protein. Haploinsufficiency of Na v 1.2 protein is one plausible explanation for the pathology of this patient; however, our biophysical findings suggest that the R102X truncated protein exerts a dominant negative effect leading to the patient's intractable epilepsy.

show abstract

“…Missense mutations in Na V 1.1 channels cause GEFSϩ (generalized epilepsy with febrile seizures plus), a dominantly inherited seizure disorder (Escayg et al, 2001;Wallace et al, 2001), and loss-of-function mutations in Na V 1.1 channels cause severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome), which is genetically dominant (Sugawara et al, 2002;Claes et al, 2003;Fukuma et al, 2004). Like SMEI patients, knock-out (KO) mice lacking Na V 1.1 channels suffer severe epilepsy and premature death (Yu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Kalume¹,

Yu²,

Westenbroek³

et al. 2007

J. Neurosci.

237

251

View full text Add to dashboard Cite

Loss-of-function mutations of Na V 1.1 channels cause severe myoclonic epilepsy in infancy (SMEI), which is accompanied by severe ataxia that contributes substantially to functional impairment and premature deaths. Mutant mice lacking Na V 1.1 channels provide a genetic model for SMEI, exhibiting severe seizures and premature death on postnatal day 15. Behavioral assessment indicated severe motor deficits in mutant mice, including irregularity of stride length during locomotion, impaired motor reflexes in grasping, and mild tremor in limbs when immobile, consistent with cerebellar dysfunction. Immunohistochemical studies showed that Na V 1.1 and Na V 1.6 channels are the primary sodium channel isoforms expressed in cerebellar Purkinje neurons. The amplitudes of whole-cell peak, persistent, and resurgent sodium currents in Purkinje neurons were reduced by 58 -69%, without detectable changes in the kinetics or voltage dependence of channel activation or inactivation. Nonlinear loss of sodium current in Purkinje neurons from heterozygous and homozygous mutant animals suggested partial compensatory upregulation of Na V 1.6 channel activity. Current-clamp recordings revealed that the firing rates of Purkinje neurons from mutant mice were substantially reduced, with no effect on threshold for action potential generation. Our results show that Na V 1.1 channels play a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of sodium current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice and SMEI patients may be sufficient to cause their ataxia and related functional deficits.

show abstract

Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy

Cited by 222 publications

References 9 publications

Physiologic Principles Underlying Ion Channelopathies

Physiologic Principles Underlying Ion Channelopathies

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Contact Info

Product

Resources

About

Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy

Cited by 222 publications

References 9 publications

Physiologic Principles Underlying Ion Channelopathies

Physiologic Principles Underlying Ion Channelopathies

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Contact Info

Product

Resources

About

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy