title: A novel Caspr mutation causes the shambling mouse phenotype by disrupting axoglial interactions of myelinated nerves.
abstract: The neurological mouse mutation shambling (shm) exhibits ataxia and hindlimb paresis. Positional cloning of shm showed that it encodes contactin-associated protein (Caspr), which is required for formation of the paranodal junction in myelinated nerves. The shm mutation is a TT insertion in the Caspr gene that results in a frame shift and a premature stop codon at the COOH-terminus. The truncated Caspr protein that is generated lacks the transmembrane and cytoplasmic domains. Here, we found that the nodal/paranodal axoplasm of shm mice lack paranodal junctions and contain large mitochondria and abnormal accumulations of cytoplasmic organelles that indicate altered axonal transport. Immunohistochemical analysis of mutant mice showed reduced expression of Caspr, contactin, and neurofascin 155, which are thought to form a protein complex in the paranodal region; protein 4.1B, however, was normally distributed. The mutant mice had aberrant localization of voltage-gated ion channels on the axolemma of nodal/paranodal regions. Electrophysiological analysis demonstrated that the velocity of saltatory conduction was reduced in sciatic nerves and that the visual response was attenuated in the primary visual cortex. These abnormalities likely contribute to the neurological phenotype of the mutant mice.
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Xiao-yang
authors.initials: XY
authors.lastname: Sun
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
authors.forename: Erina
authors.initials: E
authors.lastname: Okabe
authors.forename: Yûko
authors.initials: Y
authors.lastname: Chishima
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kanou
authors.forename: Shiori
authors.initials: S
authors.lastname: Murase
authors.forename: Kazue
authors.initials: K
authors.lastname: Mizumura
authors.forename: Mie
authors.initials: M
authors.lastname: Inaba
authors.forename: Yukio
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.forename: Sen-ichi
authors.initials: S
authors.lastname: Oda
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000737:chemistry / Q000473:pathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D009154:Mutation; D009186:Myelin Sheath / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000737:chemistry / Q000473:pathology*; D009457:Neuroglia / Q000737:chemistry / Q000473:pathology*; D010641:Phenotype
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse