拉富雷氏肌阵挛性癫痫
中文名称
通路描述
拉富雷氏病是一种进行性神经退行性疾病，通常在儿童晚期发病，以发作和神经系统恶化及死亡为特征，发病后十年内死亡。已发现 EPM2A（拉富雷蛋白）和 NHLRC1（马林蛋白）的隐性突变是疾病的原因。该疾病在此分类为糖原贮积病，因为 EPM2A（拉富雷蛋白）和 NHLRC1（马林蛋白）调节正常的糖原周转，任一蛋白质的缺陷都与组织（包括大脑、肌肉、肝脏和心脏）中形成拉富雷体的异常不溶性糖原分子的积累有关（Ramachandran et al. 2009; Roach et al. 2012）。与疾病中糖原积累的中心作用一致，小鼠模型中糖原合酶活性降低（Turnbull et al. 2011）或缺失（Pederson et al. 2013）可防止拉富雷氏病。类型 2A 疾病。EPM2A（拉富雷蛋白）与细胞质糖原颗粒相关，通常催化添加的磷酸基团极少但一致地从生长糖原分子上移除（Tagliabracci et al. 2011）。这种催化活动的缺陷导致形成磷酸化糖原分子，这些分子不溶且具有异常的分支模式（Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011）。类型 2B 疾病。NHLRC1（马林蛋白）通常介导 EPM2A（拉富雷蛋白）和 PPP1R3C（PTG）的多泛素化。这两种泛素化蛋白被蛋白酶体介导降解，留下与糖原合酶相关的糖原 - 糖原连接蛋白颗粒。在没有 NHLRC1 活性的情况下，EPM2A 和 PPP1R3C 蛋白似乎持续存在，与异常稳定的糖原颗粒（拉富雷体）的形成有关（Chan et al. 2003; Gentry et al. 2005）。在 NHLRC1 敲除小鼠中，PPP1R3C 水平未增加而是保持不变，表明 NHLRC1 不将 PPP1R3C 靶向降解。然而，该敲除小鼠中 EPM2A 蛋白水平增加，这与 NHLRC1 所提议的作用一致（DePaoli-Roach et al. 2010）。
英文描述
Myoclonic epilepsy of Lafora Lafora disease is a progressive neurodegenerative disorder with onset typically late in childhood, characterized by seizures and progressive neurological deterioration and death within ten years of onset. Recessive mutations in EPM2A (laforin) and NHLRC1 (malin) have been identified as causes of the disease. The disease is classified here as one of glycogen storage as EPM2A (laforin) and NHLRC1 (malin) regulate normal glycogen turnover and defects in either protein are associated with the formation of Lafora bodies, accumulations of abnormal, insoluble glycogen molecules in tissues including brain, muscle, liver, and heart (Ramachandran et al. 2009; Roach et al. 2012). Consistent with a central role for glycogen accumulation in the disease, reduced (Turnbull et al. 2011) or absent (Pederson et al. 2013) glycogen synthase activity prevents Lafora Disease in mouse models.Type 2A disease. EPM2A (laforin) associated with cytosolic glycogen granules, normally catalyzes the removal of the phosphate groups added rarely but consistently to growing glycogen molecules (Tagliabracci et al. 2011). Defects in this catalytic activity lead to the formation of phosphorylated glycogen molecules that are insoluble and that show abnormal branching patterns (Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011).Type 2B disease. NHLRC1 (malin) normally mediates polyubiquitination of EPM2A (laforin) and PPP1R3C (PTG). The two polyubiquitinated proteins are targeted for proteasome-mediated degradation, leaving a glycogen-glycogenin particle associated with glycogen synthase. In the absence of NHLRC1 activity, EPM2A and PPP1R3C proteins appear to persist, associated with the formation of abnormal, stable glycogen granules (Lafora bodies) (Chan et al. 2003; Gentry et al. 2005). In NHLRC1 knockout mice PPP1R3C levels are unchanged rather than increased, suggesting that NHLRC1 does not target PPP1R3C for degradation. However, EPM2A protein levels are increased in this knockout consistent with NHLRC1's proposed role (DePaoli-Roach et al. 2010).
所含基因
7 个基因