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The mouse neurological mutant 'motor endplate disease' (med) is characterized by early onset progressive paralysis of the hind limbs, severe muscle atrophy, degeneration of Purkinje cells and juvenile lethality. We have isolated a voltage-gated sodium channel gene, Scn8a, from the flanking region of a transgene-induced allele of med. Scn8a is expressed in(More)
Infantile spasms syndrome (ISS) is a catastrophic pediatric epilepsy with motor spasms, persistent seizures, mental retardation, and in some cases, autism. One of its monogenic causes is an insertion mutation [c.304ins (GCG)(7)] on the X chromosome, expanding the first polyalanine tract of the interneuron-specific transcription factor Aristaless-related(More)
The voltage-gated sodium channel SCN8A is associated with inherited neurological disorders in the mouse that include ataxia, dystonia, severe muscle weakness, and paralysis. We report the complete coding sequence and exon organization of the human SCN8A gene. The predicted 1980 amino acid residues are distributed among 28 exons, including two pairs of(More)
Allelic mutations of Scn8a in the mouse have revealed the range of neurological disorders that can result from alternations of one neuronal sodium channel. Null mutations produce the most severe phenotype, with motor neuron failure leading to paralysis and juvenile lethality. Two less severe mutations cause ataxia, tremor, muscle weakness, and dystonia. The(More)
Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1,2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13-qter (refs 1,2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an(More)
Ca2+ currents, especially those activated at low voltages (LVA), influence burst generation in thalamocortical circuitry and enhance the abnormal rhythmicity associated with absence epilepsy. Mutations in several genes for high-voltage-activated (HVA) Ca2+ channel subunits are linked to spike-wave seizure phenotypes in mice; however, none of these mutations(More)
PURPOSE Clinical features associated with chromosome 1p36 deletion include characteristic craniofacial abnormalities, mental retardation, and epilepsy. The presence and severity of specific phenotypic features are likely to be correlated with loss of a distinct complement of genes in each patient. We hypothesize that hemizygous deletion of one, or a few,(More)
Neuronal voltage-dependent Ca2+ channels are heteromultimers of alpha1, beta, and alpha2delta subunits, and any one of five alpha1 subunits (alpha1A-E) may associate with one of four beta subunits (beta1-4). The specific alpha1-beta combination assembled determines single-channel properties, while variation in the proportion of each combination contributes(More)
Genetic analyses of familial epilepsies over the past decade have identified mutations in several different ion channel genes that result in neonatal or early-onset seizure disorders, including benign familial neonatal convulsions (BFNC), generalized epilepsy with febrile seizures plus (GEFS+), and severe myoclonic epilepsy of infancy (SMEI). These genes(More)
Ca2+ channel beta subunits regulate voltage-dependent calcium currents through direct interaction with alpha 1 subunits. The beta- and alpha 1-binding motifs are conserved, and all beta subunits can stimulate current amplitude, voltage dependence, and kinetics when coexpressed with various alpha 1 subunits. We used a positional candidate approach to(More)