CLINICAL AND MOLECULAR STUDIES OF GAUCHER DISEASE

这项研究的目的是确定高谢病患者表型变异的分子基础。最初的研究针对导致高谢病的分子突变的定义，这些突变的定义是从受影响的患者中分离基因，对他们的酸性B-葡萄糖苷酶基因进行DNA测序，并鉴定导致这种疾病的各种突变。在高谢病患者中定义了超过25个错义和更复杂的突变，这些都得到了对受影响患者和家庭的临床研究的验证。这些突变通过在杆状病毒表达系统中的异源表达来影响酸性B-葡萄糖苷酶的功能，或者评估所产生的蛋白的性质的改变。然而，即使识别了这样的突变，也只能确定不完全的基因-表型相关性。事实上，对已知突变的人群进行筛查后得出的结论是，包括N370S等位基因的基因类型与非神经性高谢病的发病严格相关。其他基因类型与非神经性或神经性形式的疾病有关。此外，在非神经性变异的患者中，我们从我们的结果和全球范围的调查中确定，大约60%的N370S纯合子基因患者非常轻微地受累或没有症状，从未得到医学上的关注。这一重要的观察结果导致了对受高谢病影响的同胞对的初步收集，以分析可能倾向于这种可变表型的修饰基因。

The objective of this study is to define the molecular basis for the phenotypic variability in affected patients with Gaucher disease. The initial studies were directed to the definition of the molecular mutations that are causal to Gaucher disease and these were defined by gene isolation from affected patients, DNA sequencing of their acid B-glucosidase genes and identification of a variety of mutations causal to the disease. Over twenty-five misssense and more complex mutations were defined in Gaucher disease patients and these were verified by clinical studies of the affected patients and families. These mutations were shown to affect the acid B-glucosidase function by heterologous expression in the baculovirus expression system or the altered properties of the resultant protein were evaluated. However, even with the identification of such mutations only imperfect genotype-phenotype correlations could be ascertained. Indeed , screening of populations for known mutations led to the conclusion that genotypes that include the N370S allele were associated strictly with the onset of non-neuronopathic Gaucher disease. Other genotypes were related to either the non-neuronopathic or neuronopathic forms of the disease. In addition, among the patients with the non-neuronopathic variant, we ascertained from our results and a world-wide survey that approximately sixty percent of patients with the N370S homozygous genotype are very mildly involved or asymptomatic and never come to medical attention. This important observation has led to the initial collection of sibpairs affected with Gaucher disease for analysis of modifier genes that may predispose to this variable phenotype.