Research in this laboratory is directed toward the elucidation of the molecular defects in inherited lysosomal storage diseases and to understand the normal cellular function and processes of these enzymes. To this end, techniques of molecular biology, protein biochemistry, enzymology, mutagenesis and heterologous expression are employed to dissect the fundamental defects which are causal to the enzymological and physiological pathologies in Gaucher disease (acid b-glucosidase deficiency) and GM1-Gangliosidosis and Morquio Syndrome Type B (acid b-galactosidase deficiencies). Efforts are directed to:

1. Dissecting the structure/function relationships of both lysosomal enzyme/activator complexes using in vitro mutagenesis and characterization of the mutant proteins.
2. Elucidating the underlying basis for phenotypic variation in Gaucher disease type 1 by investigating the role of candidate modifier genes.
3. Elucidating the underlying basis for phenotypic variation resulting from defects in acid b-galactosidase through investigations of the binding affinities and catalytic site(s) of this enzyme with respect to its primary substrates: ganglioside-GM1 (accumulates in GM1-Gangliosidosis) and keratan sulfate (accumulates in Morquio Syndrome Type B).
4. Engineering more effective therapeutic agents for enzyme therapy by identification of important signals for tissue specific uptake and intracellular targeting.
5. Enhancing the ability to predict disease severity by further refinement of genotype/phenotype correlations

Grace M, Desnick R, Pastores GM. Identification and expression of acid <font face='symbol'>b</font>-glucosidase mutations causing severe type 1 and neurologic type 2 Gaucher disease in non-Jewish patients. J Clin Invest 1997 May 15; 99(10): 2530-7.

Grace M, Ashton-Prolla P, Pastores GM, Soni A, Desnick R. Non-pseudogene-derived complex acid <font face='symbol'>b</font>-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease. J Clin Invest 1999 Mar; 103(6): 817-23.