Kaasik Allen, Kuum Malle, Aonurm Anu, Kalda Anti, Vaarmann Annika, Zharkovsky Alexander
Department of Pharmacology, Centre of Excellence of Molecular and Clinical Medicine, University of Tartu, Tartu, Estonia.
Epilepsia. 2007 Apr;48(4):752-7. doi: 10.1111/j.1528-1167.2007.00985.x. Epub 2007 Feb 23.
Unverricht-Lundborg disease (EPM1) has been considered to be an autosomal-recessive disease related with loss of function mutations in the gene encoding cystatin B. Although heterozygous carriers are generally asymptomatic, earlier studies in Finnish EPM1 families have reported minor symptoms together with slight changes in the EEG recordings also in near relatives of patients. Here we tested the hypothesis that EPM1 phenotype is expressed also in heterozygous subjects using 17-month-old cystatin B deficient mice as a model of disease. Western blot analysis demonstrated a 50% decrease in cystatin B expression in the cerebellum of these animals. Heterozygous mice showed significantly impaired rotarod performance and were weaker in the grid test. Also the total seizure-rating score of heterozygous animals was higher than in wild-type mice. The stereological analysis revealed a significant decrease in the number of neurons in cerebral cortex and the granule cell layer of cerebellum. These results suggest that partial decrease in cystatin B expression in heterozygous mice could lead to the development of mild EPM1 phenotype.
翁韦里希特-伦德伯格病（EPM1）被认为是一种常染色体隐性疾病，与编码胱抑素B的基因突变导致的功能丧失有关。虽然杂合子携带者通常没有症状，但早期对芬兰EPM1家族的研究报告称，患者的近亲也有轻微症状，脑电图记录也有轻微变化。在这里，我们以17个月大的胱抑素B缺陷小鼠作为疾病模型，检验了EPM1表型在杂合子个体中也会表达的假设。蛋白质免疫印迹分析表明，这些动物小脑内胱抑素B的表达减少了50%。杂合子小鼠在转棒试验中的表现明显受损，在网格试验中也较弱。杂合子动物的总癫痫评分也高于野生型小鼠。体视学分析显示，大脑皮层和小脑颗粒细胞层中的神经元数量显著减少。这些结果表明，杂合子小鼠中胱抑素B表达的部分降低可能会导致轻度EPM1表型的出现。
