Human Molecular Genetics Advance Access originally published online on July 21, 2008
Human Molecular Genetics 2008 17(20):3166-3179; doi:10.1093/hmg/ddn213
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Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz–Jampel syndrome neuromyotonia
1 Inserm, U546, Paris, France 2 UPMC Univ Paris 06, UMR_S546, Paris, France 3 CNRS, Institut de Neurobiologie Alfred Fessard—FRC2118, Laboratoire de Neurobiologie Cellulaire et Moléculaire—UPR9040, Gif sur Yvette, France 4 Inserm, U686, Paris, France 5 Université Paris-Descartes, Paris, France 6 U.S.M. 0301-UMR 7179, MNHN/CNRS, Département Ecologie et Gestion de la Biodiversité, Muséum National d'Histoire Naturelle de Paris, Paris, France 7 Inserm, U787, Paris, France 8 Inserm, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France 9 Faculté de médecine, Université Louis Pasteur, UMRS692, Strasbourg, France 10 Département de Neurologie, Hôpital Civil de Strasbourg, Strasbourg, France 11 AP-HP, Groupe Hospitalier de la Pitié-Salpêtrière, Fédération des maladies du système nerveux et centre de référence ‘canalopathies musculaires’, Paris, France
* To whom correspondence should be addressed at: UMR S546 (INSERM-UPMC), Faculté de médecine Pierre et Marie Curie, site Pitié-Salpêtrière, 105 boulevard de l'Hôpital, 75634 Paris cedex 13, France. Tel: +33 140778158; Fax: +33 140778117; Email: nicole{at}chups.jussieu.fr
Received May 11, 2008; Accepted July 19, 2008
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.
The authors wish it to be known that, in their opinion, the second and third authors should be regarded as joint second authors.