Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

Neurobiology of Disease
Julie M JonesMiriam H Meisler

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 a...Continue Reading

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Citations

Jun 3, 2017·Neuropharmacology·Benedetta TerragniMassimo Mantegazza
Aug 23, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Polina A Egorova, Ilya B Bezprozvanny
Feb 20, 2020·International Journal of Molecular Sciences·Jun FangXiao Wang
May 5, 2018·Human Mutation·Jacy L WagnonMiriam H Meisler
Sep 12, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Laura SoléMichael M Tamkun
Feb 4, 2021·Nature Reviews. Neuroscience·Miriam H MeislerWenxi Yu
Mar 27, 2021·Physiological Reviews·Massimo MantegazzaWilliam A Catterall

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