METHODS: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy.
RESULTS: The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen.
CONCLUSIONS: The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.
方法:我们采用了分子遗传分析,激光显微解剖聚葡聚糖体和肌肉匀浆的定量质谱,对一名45岁患者的肌肉组织进行免疫组织化学和蛋白质印迹分析,该患者患有由于聚葡聚糖贮积性肌病而导致的青少年晚期近端肌无力。
结果:由于GYG1中的一种新型纯合深内含子变体(c.7992T>G),肌肉组织表现出完全不存在糖原蛋白-1,引入假外显子导致移码和提前终止密码子。聚葡聚糖体中积累的蛋白质构成糖原代谢的组成部分,蛋白质质量控制途径和结蛋白。含有聚葡聚糖体的肌纤维经常表现出正常糖原的消耗。
结论:糖原-1是一种对糖原合成启动很重要的蛋白质,导致聚葡聚糖的储存,显示几种蛋白质的积累,包括糖原合成所必需的,隔离体1/p62和desmin,反映RBCK1缺乏症的发现。这些结果表明,不同疾病之间存在共同的致病途径,表现出聚葡聚糖的储存。这些见解对这些罕见但破坏性和目前无法治愈的疾病的治疗具有意义。