A Novel Caspr Mutation Causes the Shambling Mouse Phenotype by Disrupting Axoglial Interactions of Myelinated Nerves

• Published in: Journal of neuropathology and experimental neurology Vol. 68; no. 11; pp. 1207 - 1218
• Main Authors: Sun, Xiao-yang, Takagishi, Yoshiko, Okabe, Erina, Chishima, Yûko, Kanou, Yasuhiko, Murase, Shiori, Mizumura, Kazue, Inaba, Mie, Komatsu, Yukio, Hayashi, Yoshitaka, Peles, Elior, Oda, Sen-ichi, Murata, Yoshiharu
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.11.2009; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Amino Acid Sequence; Animals; Axons - chemistry; Axons - pathology; Biological and medical sciences; Cell Adhesion Molecules, Neuronal - genetics; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Molecular Sequence Data; Mutation; Myelin Sheath - chemistry; Myelin Sheath - genetics; Myelin Sheath - pathology; Nerve Fibers, Myelinated - chemistry; Nerve Fibers, Myelinated - pathology; Nervous system (semeiology, syndromes); Neuroglia - chemistry; Neuroglia - pathology; Neurology; Phenotype; Nervous system diseases; Optic nerve; Myelin; Sciatic nerves; Interaction; Rodentia; Contactin-associated protein; Protein; Vertebrata; Phenotype; Optic nerves; Paranodes; Mammalia; Visual pathway; Mouse; Animal; Mutation; Sciatic nerve
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e3181be2e96

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 velocityof saltatory conduction was reduced in sciatic nerves and that thevisual response was attenuated in the primary visual cortex. These abnormalities likely contribute to the neurological phenotype of the mutant mice.