Mutations of voltage-gated sodium channels in movement disorders and epilepsy.
Spontaneous and induced mutations of neuronal Na+ channels in human patients and mutant mice result in a broad range of neurological-disease. Epilepsy, a disorder of neuronal hyperexcitability, has been associated with delayed inactivation of SCN2A in mice, and with altered kinetics of SCN1A in human patients. Movement disorders including tremor, ataxia, dystonia and paralysis have been observed in mice with mutations of SCN8A. Electrophysiological recordings from neurons isolated from mice with mutations in individual channels reveal the contributions of each channel to in vivo firing patterns. In addition to monogenic disease, Na+ channel mutations are likely to contribute to polygenic disease susceptibility and to normal variation in neuronal function. Advances in molecular methods coupled with genomic sequences from the Human Genome Project will permit identification of many new patient mutations and generation of animal models to dissect their physiological and cellular consequences.
Meisler
Miriam H
MH
Department of Human Genetics, University of Michigan, Ann Arbor, 48109-0618, USA.
Kearney
Jennifer A
JA
Sprunger
Leslie K
LK
MacDonald
Bryan T
BT
Buchner
David A
DA
Escayg
Andrew
A
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D004827:Epilepsy / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics*; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C100681:SCN8A protein, human; C568249:Scn1a protein, mouse; C000654500:Scn2a protein, mouse; D015222:Sodium Channels