Steinmeyer K, Klocke R, Ortland C, Gronemeier M, Jockusch H, Gründer S, Jentsch T J
Centre for Molecular Neurobiology (ZMNH), Hamburg University, Germany.
Nature. 1991 Nov 28;354(6351):304-8. doi: 10.1038/354304a0.
MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes. Purely myotonic human diseases are dominant myotonia congenita (Thomsen) and recessive generalized myotonia (Becker), whereas myotonic dystrophy is a systemic disease. Muscle hyperexcitability was attributed to defects in sodium channels and/or to a decrease in chloride conductance (in Becker's myotonia and in genetic animal models). Experimental blockage of Cl- conductance (normally 70-85% of resting conductance in muscle) in fact elicits myotonia. ADR mice are a realistic animal model for recessive autosomal myotonia. In addition to Cl- conductance, many other parameters are changed in muscles of homozygous animals. We have now cloned the major mammalian skeletal muscle chloride channel (ClC-1). Here we report that in ADR mice a transposon of the ETn family has inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains. Together with the lack of recombination between the Clc-1 gene and the adr locus, this strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia.
肌强直（骨骼肌僵硬及舒张受损）是由肌膜动作电位重复发放所引起的多种疾病的一种症状。单纯性肌强直人类疾病有显性先天性肌强直（汤姆森病）和隐性全身性肌强直（贝克尔病），而强直性肌营养不良是一种全身性疾病。肌肉兴奋性过高归因于钠通道缺陷和/或氯电导降低（在贝克尔肌强直及遗传性动物模型中）。实际上，实验性阻断氯电导（正常情况下占肌肉静息电导的70 - 85%）会引发肌强直。ADR小鼠是隐性常染色体肌强直的一种现实动物模型。除了氯电导外，纯合动物肌肉中的许多其他参数也发生了变化。我们现已克隆出主要的哺乳动物骨骼肌氯通道（ClC - 1）。在此我们报告，在ADR小鼠中，ETn家族的一个转座子已插入相应基因，破坏了其几个跨膜结构域的编码潜能。再加上Clc - 1基因与adr位点之间缺乏重组，这有力地表明缺乏功能性氯通道是小鼠肌强直的主要原因。
