Genetic heterogeneity in Gaucher disease: physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients.
Genetic heterogeneity in Gaucher disease: physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients.
复制标题
戈谢病的遗传异质性：非神经病和神经病患者培养的成纤维细胞中残留酶的物理动力学和免疫学研究。
DOI：
10.1002/ajmg.1320210316
复制
发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Desnick,RJ
中科院分区：
文献类型：
--
作者：
Grabowski,GA;Goldblatt,J;Dinur,T;Kruse,J;Svennerholm,L;Gatt,S;Desnick,RJ
为了阐明戈谢病三种主要表型亚型的遗传异质性，通过比较动力学、热稳定性和免疫滴定研究，研究了来自不同种族和人口统计学组的所有三种亚型患者的成纤维细胞中残留的酸性β-葡萄糖苷酶。动力学研究描述了三组不同的残留活性（指定为A、B和C），对酶修饰剂牛磺胆酸盐（或磷脂酰丝氨酸）和葡萄糖基鞘氨醇（或N-己基葡萄糖基鞘氨醇）具有特征性响应; A组残留酶对这些修饰剂的响应正常。所有神经元病患者（2型和3型）和大多数非犹太人、非神经元病患者（1型）具有A组残留活性，因此无法通过其动力学特性进行区分。B组残留酶对这些修饰剂有明显的异常反应。所有德系犹太人和仅2名非犹太1型患者有B组残留活动。C组残留活性对所有修饰剂有中等反应，代表单个南非白人1型患者。家系研究表明，该患者是A组（2型）和B组（1型）突变的遗传复合物。热稳定性研究表明，三个动力学组内的残留活性的额外的异质性。A组（2型）和B组（1型）酶的热稳定性降低相似。相比之下，A组（1型）残留活性是异质的;在这些酶中发现三类热稳定性：正常、降低和增加正常或戈谢病的等量β-葡萄糖苷酶活性与单特异性IgG的免疫滴定表明，大多数戈谢病患者的酶蛋白发生抗原性改变和/或存在大量催化异常或无活性抗原。在A组1型非洲黑人患者中存在抗原性和催化性正常酶的量减少，表明其突变型酸性β-葡萄糖苷酶的稳定性或合成降低。这些动力学、免疫学和热稳定性研究表明，1型（1）戈谢病在生化上具有异质性，至少是由改变酶结构和/或功能的不同等位酸β-葡萄糖苷酶突变引起的，2神经元病和非犹太人非神经元病表型不能仅通过动力学分析可靠区分，和3）Ashkenzi 1型戈谢病由改变酸性β-葡糖苷酶的特定活性位点结构域的独特突变引起。
To elucidate the genetic heterogeneity in the three major phenotypic subtypes of Gaucher disease, the residual acid β‐glucosidase in fibroblasts from patients with all three subtypes from different ethnic and demographic groups was investigated by comparative kinetic, thermostability, and immunotitration studies. The kinetic studies delineated three distinct groups (designated A, B, and C) of residual activities with characteristic responses to the enzyme modifiers, taurocholate (or phosphatidylserine), and glucosyl sphingosine (or N‐hexyl glucosyl sphingosine); Group A residual enzymes responded normally to these modifiers. All neuronopathic patients (types 2 and 3) and most non‐Jewish, non‐neuronopathic patients (type 1) had group A residual activities and thus could not be distinguished by their kinetic properties. Group B residual enzymes had markedly abnormal responses to these modifiers. All Ashkenazi and only two non‐Jewish type 1 patients had group B residual activities. Group C residual activity had an intermediate response to all modifiers and represented a single Afrikaner type 1 patient. Pedigree studies indicated that this patient was a genetic compound for the group A (type 2) and group B (type 1) mutations. Thermostability studies showed additional heterogeneity of the residual activities within the three kinetic groups. Group A (type 2) and group B (type 1) enzymes had similarily decreased thermostabilities. In contrast, group A (type 1) residual activities were heterogeneous; three classes of thermostabilities were found among these enzymes: normal, decreased, and increased Immunotitration of equal amonuts of the normal or Gaucher dieseas β‐glucosidase activities with monospecific IgG indicated that the enzyme proteins from most Gaucher disease patients were antigenically altered and/or that large amounts of catalytically abnormal or inactive antigen were present. A decreased amount of antigenically and catalytically normal enzyme was present in a group A, type 1 African black patient, suggesting decreased stability or synthesis of his mutant acid β‐glucosidase. These kinetic, immunologic, and thermostability studies indicated that 1 type (1) Gaucher disease is biochemically heterogeneous and results from at least from distinct allelic acid β‐glucosidase mutations that alter enzyme structuer and/or function, 2 neuronopathic and non‐Jewish non‐neuronopathic phenotypes cannot be distinguished reliably by kinetic analyses alone, and 3) the Ashkenzi type 1 Gaucher disease results from a unique mutation that alters a specific active site domain of acid β‐glucosidase.