GENETIC METABOLIC MYOPATHIES--PHOSPHOFRUCTOKINASE/ACID MALTASE DEFICIENCY

遗传代谢性肌病--磷酸果糖激酶/酸性麦芽糖酶缺乏症

• 批准号: 2568371
• 负责人: P H PLOTZ
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2568371
• 关键词: 6 phosphofructokinase; African; African American; European; Jewish; RNA splicing; Retroviridae; clinical research; enzyme deficiency; gene mutation; gene therapy; genetic carriers; glycogen storage disease type II; glycogen storage disease type VII; heterozygote; human subject; inborn lysosomal enzyme disorder; molecular pathology; myoblasts; transfection /expression vector

In the course of studying inflammatory muscle diseases (polymyositis, dermatomyositis, and related diseases), we have encountered patients with other muscle diseases. We have studied patients with two genetic metabolic myopathies in detail: phosphofructokinase (PFK) deficiency, and acid maltase (acid alpha-glucosidase, or GAA) deficiency. The studies of PFK deficiency were aimed at characterizing the genetic defects and the associated clinical picture in several groups of patients. The final study in the endeavor turned up the curious finding that the disease in an in-bred Swedish family from a small village was due to the propagation through a number of generations of two different disease-related mutations. Together with the fact that the largest reservoir of patients, Ashkenazi Jews, also derives from the same geographic region along the Baltic (although the mutations are different), this raises the interesting possibility that the heterozygous carrier state is advantageous in this region. Because this is a mild as well as an infrequent condition, we have ceased work on it. Acid maltase deficiency is both more frequent and more serious. It can be fatal in infancy (Pompe disease) or later in life, when a myopathy with lung disease clinically similar to myositis is fatal in middle age. The following studies are underway: 1) Careful analysis of the most common adult mutation. Studies with an in vitro model system have shown that a single base mutation in the polypyrimidine tract towards the end of intron 1 reduces the transcription rate, apparently by altering the binding of a splicing factor, and alters the ratio of splice variants to favor the splicing of non-productive mRNA. Furthermore, a silencer has been identified elsewhere in this intron, and may be a candidate for pharmacological intervention to up-regulate this gene. 2) Analysis of the mutations in clinical variants. Studies in the atypical juvenile form has turned up a disabled form of the enzyme. Studies in patients from West Africa (presenting at Children's Hospital in Washington) has shown they share the same mutation, and it is the same mutation identified in the only Afro-American patients studied. This mutation appears, therefore, to be a marker of origin from a particular West African tribe. This is being pursued in collaboration with scholars in other disciplines. 3) Gene transfer with a retroviral vector. Since acid maltase deficiency is a lysosomal storage disease, it is an attractive candidate for gene replacement. A retroviral vector has been shown not only to act in myoblasts and fibroblasts to remove lysosomal glycogen, but also to provide a similar phenotypic improvement in other affected muscle cells through the secretion-mannose-6-phosphate re-uptake pathway and through cell fusion. This suggests that a relatively small number of gene-corrected myoblasts may be able to phenotypically correct a much larger number of cells.

在研究炎症性肌肉疾病（多发性肌炎、 皮肌炎及相关疾病），我们遇到过以下患者 其他肌肉疾病。 我们研究了具有两种遗传基因的患者 代谢性肌病详细信息：磷酸果糖激酶 (PFK) 缺乏症，以及 酸性麦芽糖酶（酸性α-葡萄糖苷酶，或GAA）缺乏。 PFK 缺乏症的研究旨在表征遗传特征 几组患者的缺陷和相关的临床表现。 这项努力的最终研究得出了一个奇怪的发现： 瑞典一个小村庄的近亲家庭中发生的这种疾病是由于 通过两个不同的世代的传播 疾病相关的突变。 再加上最大的事实 病人的储存库，德系犹太人，也源自同一国家 波罗的海沿岸的地理区域（尽管突变不同）， 这提出了一个有趣的可能性，即杂合携带者 国家在该地区具有优势。 因为这是一种温和的 这是一种罕见的情况，我们已经停止了这方面的工作。 酸性麦芽糖酶缺乏症更为常见且更为严重。 它可以是 当患有肌病时，在婴儿期（庞贝病）或晚年致命 临床上类似于肌炎的肺部疾病在中年时是致命的。 这 以下研究正在进行中： 1）仔细分析最常见的 成年突变。 体外模型系统的研究表明 多嘧啶束中朝向内含子末端的单碱基突变 1 降低了转录率，显然是通过改变a的结合 剪接因子，并改变剪接变体的比例以有利于 非生产性 mRNA 的剪接。 此外，还配备了消音器 在此内含子的其他地方鉴定出，并且可能是候选者 药物干预上调该基因。 2）分析 临床变异的突变。 对非典型青少年形式的研究 发现了该酶的失效形式。 对西方患者的研究 非洲（在华盛顿儿童医院发表演讲）表明他们 共享相同的突变，并且与在 仅对非裔美国患者进行了研究。 因此，这种突变似乎 是来自特定西非部落的起源标记。 这就是正在 与其他学科的学者合作进行。 3）基因 用逆转录病毒载体进行转移。 由于酸性麦芽糖酶缺乏症是 溶酶体贮积病，它是一个有吸引力的候选基因 替代品。 逆转录病毒载体已被证明不仅可以作用于 成肌细胞和成纤维细胞去除溶酶体糖原，还可以 在其他受影响的肌肉细胞中提供类似的表型改善 通过分泌-甘露糖-6-磷酸再摄取途径并通过 细胞融合。 这表明，数量相对较少的 基因校正的成肌细胞可能能够在表型上纠正很多 细胞数量较多。