CLINICAL AND MOLECULAR STUDIES OF GAUCHER DISEASE

本研究的目的是确定戈谢病患者表型变异的分子基础。 最初的研究是针对戈谢病的病因的分子突变的定义，这些是通过从受影响的患者中分离基因，对其酸性B-葡萄糖苷酶基因进行DNA测序和鉴定导致该疾病的各种突变来定义的。 在戈谢病患者中定义了超过25个错义和更复杂的突变，这些突变通过对受影响患者和家庭的临床研究得到了证实。 这些突变显示通过在杆状病毒表达系统中的异源表达影响酸性B-葡糖苷酶功能，或评价所得蛋白质的改变性质。 然而，即使鉴定出这样的突变，也只能确定不完全的基因型-表型相关性。 事实上，对已知突变的人群进行筛查得出的结论是，包括N370 S等位基因的基因型与非神经病性戈谢病的发病密切相关。 其他基因型与非神经病性或神经病性形式的疾病有关。 此外，在非神经元病性变异的患者中，我们从我们的结果和一项世界范围的调查中确定，大约60%的N370 S纯合基因型患者的病情非常轻微或无症状，从未就医。 这一重要的观察结果导致了最初收集的同胞与戈谢病的修饰基因，可能易患这种可变表型的分析。

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.