DEFICIENCY OF THE HEXOSAMINIDASE-A ACTIVATOR PROTEIN IN A CASE OF GM2 GANGLIOSIDOSIS - VARIANT-AB
DEFICIENCY OF THE HEXOSAMINIDASE-A ACTIVATOR PROTEIN IN A CASE OF GM2 GANGLIOSIDOSIS - VARIANT-AB
复制标题
DOI：
10.1203/00006450-198203000-00011
复制
发表时间：
1982-01-01
影响因子：
3.6
通讯作者：
KIN, NMKNY
中科院分区：
文献类型：
--
作者：
HECHTMAN, P;GORDON, BA;KIN, NMKNY
本文描述了一例婴儿，其临床病程和病理特征，包括灰质中大量的GM2神经节苷脂储存，与经典的Tay-Sachs病相同，尽管β-N-乙酰氨基己糖苷酶水平正常，同工酶分布正常。患者S氨基己糖苷酶的动力学性质和耐热性正常。病人S死后肝脏的粗提物可催化5.1pmols标记的神经节苷脂每毫克蛋白16h的水解(对照肝脏=69.9pmoles/16h/mg)。加入部分纯化的人肝己糖氨酸酶A激活蛋白可刺激患者肝脏提取液对底物的水解率为27倍，而对照肝脏为3倍。对S患者和对照肝脏浓缩部分激活剂的测定表明，氨基己糖苷酶A催化GM2神经节苷脂和Asialo-GM2神经节苷脂的水解量减少(对照组的25%-30%)。在反应混合物中加入鞘磷脂，可以抑制表面活性物质对氨基己糖苷酶A的刺激，将患者S肝脏制剂对氨基己糖苷酶A的激活降低到无法检测的水平。对照和患者S肝脏浓缩制剂的聚丙烯酰胺凝胶电泳图显示，对照肝脏中有一条与激活蛋白相对应的快速迁移蛋白条带，而患者S肝脏中没有这条蛋白条带。该患者可能是典型泰-萨克斯病的基因复制者，其原因是控制己糖氨酸酶A激活蛋白表达的基因发生突变。体内溶酶体水解酶对鞘磷脂底物水解酶活性蛋白的需求可能解释了在使用合成亲水性底物进行检测时，纯合子中存在正常水平的酶的其他贮藏疾病实体的发生。
An infant is described whose clinical course and pathologic features, including massive brain storage of GM2 ganglioside in grey matter, are identical with those of classical Tay-Sachs disease despite normal levels of .beta.-N-acetyl hexosaminidase and normal isozyme distribution. The kinetic properties and thermolability of the patient''s hexosaminidase are normal. Crude extracts of a postmortem sample of patient''s liver can catalyze the hydrolysis of 5.1 pmoles of labeled GM2 ganglioside/16 h per mg of protein (control liver = 69.9 pmoles/16 h per mg). Addition of partially purified human liver hexosaminidase A activator protein stimulated the hydrolysis of substrate by the patients liver extract by 27-fold, compared to 3-fold for control livers. Measurement of activator in enriched fractions of patient''s and control liver showed a reduced (25-30% of control) amount of stimulation of hexosaminidase A catalyzed hydrolysis of GM2 ganglioside as well as of Asialo-GM2 ganglioside. The addition of sphingomyelin to reaction mixtures, which is known to inhibit surfactant stimulation of hexosaminidase A, reduced activation of hexosaminidase A by patient''s liver preparation to undetectable levels. Polyacrylamide gel electrophoresis of enriched preparations of control and patient''s liver showed a rapidly migrating protein band in control liver corresponding to the activator protein and the absence of this protein band in the patient''s liver. This patient is probably a genocopy of classical Tay-Sachs disease as a result of a mutation at a gene locus controlling the expression of the hexosaminidase A activator protein. The in vivo requirement of activator protein for hydrolysis of sphingolipid substrates by lysosomal hydrolases may explain the occurrence of other storage disease entities in which normal levels of enzyme are present in the homozygote when assayed using synthetic hydrophilic substrates.