title: A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline.
abstract: Mutations, exclusively missense, of voltage-gated sodium channel alpha 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.
authors.affiliation: Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Kazusaku
authors.initials: K
authors.lastname: Kamiya
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaneda
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugawara
authors.forename: Emi
authors.initials: E
authors.lastname: Mazaki
authors.forename: Nami
authors.initials: N
authors.lastname: Okamura
authors.forename: Mauricio
authors.initials: M
authors.lastname: Montal
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Fukushima
authors.forename: Tateki
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
mesh_terms: D000328:Adult; D001321:Autistic Disorder / Q000150:complications / Q000235:genetics; D002460:Cell Line; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D006801:Humans; D006948:Hyperkinesis / Q000150:complications / Q000235:genetics; D008607:Intellectual Disability / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C568251:SCN2A protein, human; D015222:Sodium Channels