Study for pathogenesis of Schwartz-Jampel syndrome using mouse model.

Schwartz-Jampel综合征（SJS）是由perlecan部分功能突变引起的，以肌强直和轻度软骨发育不良为特征。我们之前已经证明，perlecan是将乙酰胆碱酯酶（AChE）定位到神经肌肉连接处（NMJ）所必需的。为了探讨perlecan缺陷引起的肌强直的机制，我们在软骨特异性启动子的控制下，通过在软骨中特异性表达重组perlecan，建立了挽救perlecan缺失小鼠围产期死亡的小鼠模型。突变小鼠存活了下来，但出现了肌强直，肌电图显示持续放电和肌肉变性，这是SJS的特征。用乙酰胆碱受体（AChR）阻滞剂curare治疗可阻断放电。A型肉毒毒素，它能抑制神经末梢乙酰胆碱的释放。应用Curare减轻眼轮匝肌强直。这些结果表明，这些突触前异常和突触后肌肉缺陷的结合导致了perlecn -null肌的持续收缩。建立的小鼠模型有助于研究肌强直的发病机制和开发治疗药物。

Schwartz-Jampel syndrome (SJS), characterized by myotonia and mildchondrodysplasiais, is caused by partially functional mutations of perlecan. We previously demonstrated that perlecan is essential for localizing acetylcholinesterase (AChE) to neuromuscular junction (NMJ). To investigate the mechanism of myotonia caused by perlecan defects, we have created a mouse model by rescuing the perinatal lethality of perlecan-null mice by expressing recombinant perlecan specifically in cartilage under the control of a cartilage-specific promoter. The mutant mice survived but developed myotonia, which showed a continuous discharge on the EMG (electromyography) and degeneration of muscle, characteristics to SJS. The discharge was blocked by treatment with curare, an acetylcholine receptor (AChR) blocker. botulinumtoxin type A, which inhibits the release of ACh from the nerve terminal. Curare application reduced myotonia in orbicularis oculi muscles. These results suggest that a combination of these presynaptic abnormalities and postsynaptic muscle defects causes a continuous contraction of perlecan-null muscle. Our mouse model is useful to study the mechanism of myotonia and to develop therapeutic agents for the disease.