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The elucidation of pathomechanism and the development of therapy of myopathies with autophagic abnormalities

自噬异常肌病的发病机制阐明及治疗进展

基本信息

批准号：
13470138
负责人：
NISHINO Ichizo
金额：
$ 7.81万
依托单位：
NATIONAL INSTITUTE OF NEUROSCIENE, NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY (NCNP)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We clinicopathologically characterized 38 patients from 13 distinct families with genetically confirmed Danon disease. Cardiomyopathy and myopathy were seen in all men but mental retardation was present in 70% of men. Serum CK level is elevated in all men but only in 63% of women. Men died at age 19±6 years while women died at age 40±7 years, both due to cardiac failure. All women developed lethal cardiomyopathy even though they had milder symptoms. We identified two new forms of autophagic vacuolar myopathy (AVM) which resembles Danon disease but are genetically distinct : adult-onset AVM with multi-organ involvement and X-linked AVM resembling congenital myopathy. The latter disease was mapped to Xq28. LC3,which is supposed to be degraded immediately after the fusion between autophagosomes and lysosomes, was not degraded in the X-linked AVM, suggesting an abnormality in the degradation process.We identified that the GNE gene encoding UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK) is the causative gene for distal myopathy with rimmed vacuoles (DMRV) just as in hereditary inclusion body myopathy. Recombinant proteins with mutations found in patients showed that those with mutations in GNE domain had decreased GNE activity while those with MNK mutations had decreased MNK activity.Sialylation was decreased in patients' cells, which was recovered by adding ManNAc or NeuAc. Our results suggest a possibility of curative therapy for DMRV.

我们对来自13个不同家族的38例遗传学证实为Danon病的患者进行了临床病理学分析。所有男性均出现心肌病和肌病，但70%的男性存在智力低下。所有男性血清CK水平升高，但仅63%的女性升高。男性死于19±6岁，女性死于40±7岁，均死于心力衰竭。所有的妇女都患上了致命的心肌病，即使她们的症状较轻。我们发现了两种新形式的自噬空泡性肌病（AVM），类似于Danon病，但在遗传上是不同的：成人发病的AVM与多器官受累和X连锁AVM类似于先天性肌病。后一种疾病被定位到Xq 28。LC 3在X连锁AVM中没有降解，提示降解过程异常，我们鉴定了编码UDP-GlcNAc 2-差向异构酶/ManNAc激酶（GNE/MNK）的GNE基因是有缘空泡远端肌病（DMRV）的致病基因，与遗传性包涵体肌病一样。在患者体内发现突变的重组蛋白，GNE结构域突变的重组蛋白GNE活性降低，MNK结构域突变的重组蛋白MNK活性降低，患者细胞唾液酸化功能降低，加入ManNAc或NeuAc后唾液酸化功能恢复。我们的研究结果表明，DMRV的治愈性治疗的可能性。