title: Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder.
abstract: Mutations of the neuronal sodium channel gene SCN8A are associated with lethal movement disorders in the mouse and with human epileptic encephalopathy. We describe a spontaneous mouse mutation, Scn8a(9J), that is associated with a chronic movement disorder with early onset tremor and adult onset dystonia. Scn8a(9J) homozygotes have a shortened lifespan, with only 50% of mutants surviving beyond 6 months of age. The 3 bp in-frame deletion removes 1 of the 3 adjacent isoleucine residues in transmembrane segment DIVS6 of Nav1.6 (p.Ile1750del). The altered helical orientation of the transmembrane segment displaces pore-lining amino acids with important roles in channel activation and inactivation. The predicted impact on channel activity was confirmed by analysis of cerebellar Purkinje neurons from mutant mice, which lack spontaneous and induced repetitive firing. In a heterologous expression system, the activity of the mutant channel was below the threshold for detection. Observations of decreased nerve conduction velocity and impaired behavior in an open field are also consistent with reduced activity of Nav1.6. The Nav1.6Δ1750 protein is only partially glycosylated. The abundance of mutant Nav1.6 is reduced at nodes of Ranvier and is not detectable at the axon initial segment. Despite a severe reduction in channel activity, the lifespan and motor function of Scn8a(9J/9J) mice are significantly better than null mutants lacking channel protein. The clinical phenotype of this severe hypomorphic mutant expands the spectrum of Scn8a disease to include a recessively inherited, chronic and progressive movement disorder.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Jones
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States.
authors.forename: Louise
authors.initials: L
authors.lastname: Dionne
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: James
authors.initials: J
authors.lastname: Dell'Orco
authors.affiliation: Department of Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Parent
authors.affiliation: Department of Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Krueger
authors.affiliation: Department of Neurology and Centre for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06516, United States. Electronic address: xycheng@shsmu.edu.cn.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Neurology and Centre for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06516, United States.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Rosie K
authors.initials: RK
authors.lastname: Bunton-Stasyshyn
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sharkey
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
authors.affiliation: Department of Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Murphy
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Shakkottai
authors.affiliation: Department of Neurobiology & Anatomy, University of Rochester Medical Center, Rochester, NY 14642, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Shrager
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: meislerm@umich.edu.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
mesh_terms: D000200:Action Potentials; D000596:Amino Acids / Q000235:genetics*; D000818:Animals; D000071040:Axon Initial Segment / Q000378:metabolism; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D004421:Dystonia / Q000150:complications / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009069:Movement Disorders / Q000150:complications / Q000235:genetics* / Q000662:veterinary; D053580:Muscle Strength; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000502:physiology; D009431:Neural Conduction; D009469:Neuromuscular Junction / Q000473:pathology; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology; D011901:Ranvier's Nodes / Q000378:metabolism; D017384:Sequence Deletion; D016019:Survival Analysis; D014202:Tremor / Q000150:complications / Q000235:genetics
chemical_list: D000596:Amino Acids; D062557:NAV1.6 Voltage-Gated Sodium Channel; C491046:Scn8a protein, mouse
keywords: Axon initial segment; Glycosylation; Movement disorder; Na(v)1.6; Nodes of Ranvier; Purkinje cell; Scn8a; Transmembrane segment; Voltage-gated sodium channel