title: Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia.
abstract: Schwartz-Jampel syndrome (SJS) is a recessive neuromyotonia with chondrodysplasia. It results from hypomorphic mutations of the gene encoding perlecan, leading to a decrease in the levels of this heparan sulphate proteoglycan in basement membranes (BMs). It has been suggested that SJS neuromyotonia may result from endplate acetylcholinesterase (AChE) deficiency, but this hypothesis has never been investigated in vivo due to the lack of an animal model for neuromyotonia. We used homologous recombination to generate a knock-in mouse strain with one missense substitution, corresponding to a human familial SJS mutation (p.C1532Y), in the perlecan gene. We derived two lines, one with the p.C1532Y substitution alone and one with p.C1532Y and the selectable marker Neo, to down-regulate perlecan gene activity and to test for a dosage effect of perlecan in mammals. These two lines mimicked SJS neuromyotonia with spontaneous activity on electromyogramm (EMG). An inverse correlation between disease severity and perlecan secretion in the BMs was observed at the macroscopic and microscopic levels, consistent with a dosage effect. Endplate AChE levels were low in both lines, due to synaptic perlecan deficiency rather than major myofibre or neuromuscular junction disorganization. Studies of muscle contractile properties showed muscle fatigability at low frequencies of nerve stimulation and suggested that partial endplate AChE deficiency might contribute to SJS muscle stiffness by potentiating muscle force. However, physiological endplate AChE deficiency was not associated with spontaneous activity at rest on EMG in the diaphragm, suggesting that additional changes are required to generate such activity characteristic of SJS.
authors.affiliation: Inserm, U546, Univ Paris 06, Paris, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Stum
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girard
authors.forename: Marie
authors.initials: M
authors.lastname: Bangratz
authors.forename: Véronique
authors.initials: V
authors.lastname: Bernard
authors.forename: Marc
authors.initials: M
authors.lastname: Herbin
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.forename: Claire-Sophie
authors.initials: CS
authors.lastname: Davoine
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
authors.forename: Christophe
authors.initials: C
authors.lastname: Marcel
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Eric
authors.initials: E
authors.lastname: Krejci
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
mesh_terms: D000110:Acetylcholinesterase / Q000172:deficiency* / Q000235:genetics*; D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004576:Electromyography; D005260:Female; D018628:Gene Dosage; D019812:Heparan Sulfate Proteoglycans / Q000172:deficiency / Q000235:genetics; D006801:Humans; D020386:Isaacs Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009045:Motor Endplate / Q000201:enzymology* / Q000503:physiopathology; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype
chemical_list: D019812:Heparan Sulfate Proteoglycans; C071927:perlecan; D000110:Acetylcholinesterase