Maple syrup urine disease: It has come a long way
Maple syrup urine disease: It has come a long way
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DOI：
10.1016/s0022-3476(98)70523-2
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发表时间：
1998-03-01
影响因子：
5.1
通讯作者：
Chuang, DT
中科院分区：
文献类型：
--
作者：
Chuang, DT
枫糖浆尿病（Maple syrup urine disease， MSUD）于1954年由Menkes等人首次描述为一种进行性神经退行性疾病。1960年，Dancis等人发现MSUD的代谢障碍是源自亮氨酸、异亮氨酸和缬氨酸的支链a-酮酸的脱羧。受MSUD影响的多酶复合物，线粒体支链α -酮酸（BCKD）脱氢酶复合物于1978年在Freed的实验室进行了纯化。这导致后来克隆了人类BCKD复合物亚基的cdna和基因。MSUD的遗传异质性现在可以通过BCKD复合体的E1 α、E1 β、E2和E3位点发生的各种突变来解释。最近，我们发现细菌伴侣蛋白GroEL和GroES在大肠杆菌中促进BCKD复合物E1脱羧酶组分的折叠和组装。该系统中的脉冲追踪标记显示，E1 α突变亚群，特别是Mennonite MSUD患者中的纯合子y393n - α，阻碍了突变E1 α亚基与正常E1 β的组装。装配缺陷与MSUD细胞中正常E1 β亚基的快速降解有关。逆转录病毒介导的来自门诺派MSUD患者正常E1 α cDNA的淋巴母细胞转导导致BCKD活性完全恢复。这伴随着正常E1 β亚基的稳定，通过重组E1 α组装。结果证明了E1 α缺陷（IA型）MSUD稳定校正的可行性，为基因治疗的发展提供了依据。
Maple syrup urine disease (MSUD) was first described in 1954 by Menkes et al. as a progressive neurologic degenerative disorder. In 1960, Dancis et al. established that the metabolic block in MSUD is at the decarboxylation of branched chain a-ketoacids derived from leucine, isoleucine, and valine. The multienzyme complex affected in MSUD, the mitrochondrial branched-chain alpha-ketoacid (BCKD) dehydrogenase complex was purified in 1978 to homogeneity in Freed's laboratory. This led to the later cloning of cDNAs and genes for subunits of the human BCKD complex. Genetic heterogeneity in MSUD is now explained by the various mutations that occur in the E1 alpha, E1 beta, E2, and E3 loci of the BCKD complex. Recently, we found that bacterial chaperonins GroEL and GroES promote folding and assembly of E1 decarboxylase component of the BCKD complex in Escherichia coli. Pulse-chase labeling in this system showed that a subset of E1 alpha mutations, notably the homozygous Y393N-alpha in Mennonite MSUD patients, impedes the assembly of the mutant E1 alpha subunit with normal E1 beta. The assembly defect is associated with a rapid degradation of the normal E1 beta subunit in MSUD cells. Retrovirus-mediated transduction of lymphoblasts from a Mennonite MSUD patient with a normal E1 alpha cDNA resulted in a complete restoration of BCKD activity. This was accompanied by a stabilization of the normal E1 beta subunit through assembly with recombinant E1 alpha. The results demonstrated the feasibility of stable correction of E1 alpha-deficient (type IA) MSUD and provided a basis for the development of gene therapy.