title: A mouse model of Schwartz-Jampel syndrome reveals myelinating Schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking.
abstract: Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K(+) channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K(+) homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes.
authors.affiliation: INSERM, U975, Research Center of the Brain and Spinal Cord Institute, U975, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bangratz
authors.forename: Nadège
authors.initials: N
authors.lastname: Sarrazin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devaux
authors.forename: Désirée
authors.initials: D
authors.lastname: Zambroni
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
authors.forename: Delphine
authors.initials: D
authors.lastname: Boërio
authors.forename: Claire-Sophie
authors.initials: CS
authors.lastname: Davoine
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Evelyne
authors.initials: E
authors.lastname: Benoit
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000375:Aging / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology*; D001485:Basement Membrane / Q000378:metabolism; D003711:Demyelinating Diseases / Q000209:etiology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D019812:Heparan Sulfate Proteoglycans / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051662:Kv1.1 Potassium Channel / Q000096:biosynthesis; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009154:Mutation; D009186:Myelin Sheath / Q000502:physiology / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000503:physiopathology; D010009:Osteochondrodysplasias / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D011901:Ranvier's Nodes / Q000378:metabolism / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology*; D012584:Sciatic Nerve / Q000503:physiopathology / Q000648:ultrastructure
chemical_list: D019812:Heparan Sulfate Proteoglycans; C071927:perlecan; D051662:Kv1.1 Potassium Channel