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.
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