We approached the characterization of the mutations responsible for inherited neurological or psychiatric disorders by studying the gene organization of specific proteins that might have a role in the pathogenesis of the clinical manifestations. Using the inherited lysosomal storage disorders, Gaucher disease and Fabry disease, as models, we demonstrated that the phenotypic heterogeneity seen within these inherited disorders is a consequence of different mutations, each affecting protein activity and influencing the processing, compartmentalization and/or stability of the protein. Recombinant DNA techniques have been used to elucidate the structure of the gene for the proteins involved in these disorders. Restriction fragment length polymorphisms (RFLPs) have been identified that are useful for the identification of a mutation in Gaucher disease which frequently occurs in neuronopathic phenotypes. Northern blot analysis provides further details of the structure of the normal and mutant genes. The molecular mechanisms leading to nervous system involvement in these disorders have also been investigated. The results of this research should provide a more rational foundation for the diagnosis and formulation of therapeutic strategies for these inherited disorders.
