STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES

HEXA、HEXB和GM 2A这三种基因中的任何一种突变都会导致 GM 2神经节苷脂沉积症是一组严重的神经退行性疾病。 我们正在创建这些遗传疾病的模型 通过在小鼠体内靶向基因破坏。 HEXA-我们已经产生了具有生化和神经病理学特征的小鼠 通过破坏编码α的Hexa基因来治疗泰-萨克斯病 β-氨基己糖苷酶A亚基。 突变小鼠显示出少于 1%的正常β-氨基己糖苷酶A（β-hex A）活性，并累积 GM 2神经节苷脂在脑中以年龄依赖的方式。 累计 神经节苷脂以膜性胞浆体的形式存在于神经元中 典型地存在于泰-萨克斯病患者的神经元中。 HEXB -编码β-hex A的β亚基的Hexb基因已经被证实是 在胚胎干细胞和嵌合小鼠中被破坏。 当人类的同源基因有缺陷时， 结果 GM 2A-GM 2激活蛋白与GM 2形成底物复合物 能够通过β-hex A降解神经节苷脂的神经节苷脂。 人GM 2激活蛋白基因的突变导致GM 2 AB型神经节苷脂沉积症 我们分离并测序了一个全长的 小鼠GM 2激活蛋白cDNA。 Gm 2a基因定位于一个区域， 在小鼠11号染色体上，它与人类的一段同源， 5号染色体上含有人类正染色体基因。 此外，Gm 2a 相关序列（Gm 2a-rsl）被定位到小鼠5号染色体上。

Mutations in any of three genes, HEXA, HEXB and GM2A, result in forms of the GM2 gangliosidoses, a group of severe neurodegenerative diseases. We are in the process of creating models of these genetic disorders through targeted gene disruption in the mouse. HEXA- We have produced mice with biochemical and neuropathologic features of Tay-Sachs disease by disruption of the Hexa gene encoding the alpha subunit of beta-hexosaminidase A. The mutant mice displayed less than 1% of normal beta-hexosaminidase A (beta-hex A) activity and accumulated GM2 ganglioside in brain in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. HEXB - The Hexb gene encoding the beta subunit of beta-hex A has been disrupted in embryonic stem cells and chimeric mice have been derived. When the homologous gene is defective in humans, Sandhoff disease results. GM2A - The GM2 activator protein forms a substrate-complex with GM2 ganglioside which enables degradation of the ganglioside by beta-hex A. Mutations in the human GM2 activator protein gene result in the GM2 gangliosidosis AB variant. We have isolated and sequenced a full-length mouse GM2 activator protein cDNA. The Gm2a gene was mapped to a region on mouse Chromosome 11 that is homologous with a segment of human chromosome 5 containing the orthologous human gene. In addition, a Gm2a related sequence (Gm2a-rsl) was mapped to mouse Chromosome 5.