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 名患者进行了临床病理学特征分析，所有男性均患有心肌病和肌病，但 70% 的男性存在智力低下，但所有男性中只有 63% 的血清 CK 水平升高。男性死于 19±6 岁，女性死于 40±7 岁，均死于心力衰竭，尽管她们的症状较轻。确定了两种新形式的自噬性空泡肌病（AVM），类似于 Danon 病，但在遗传上有所不同：成人发病的多器官受累的 AVM 和类似于先天性肌病的 X 连锁 AVM，后者被映射到 Xq28。本应在自噬体和溶酶体融合后立即降解，但在 X 连锁 AVM 中并未降解，表明自噬体和溶酶体融合后存在异常我们发现编码 UDP-GlcNAc 2-差向异构酶/ManNAc 激酶 (GNE/MNK) 的 GNE 基因是带有边缘空泡的远端肌病 (DMRV) 的致病基因，就像在遗传性包涵体肌病中发现的重组蛋白突变一样。在患者中发现，GNE 结构域突变的患者 GNE 活性降低，而 MNK 突变的患者 MNK 活性降低。患者的唾液酸化降低细胞，通过添加 ManNAc 或 NeuAc 来回收。我们的结果表明了 DMRV 治愈的可能性。