Promising results of the chaperone effect caused by imino sugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease.

Gaucher disease is an autosomal recessive disorder. It is characterized by the accumulation of glucosylceramide in lysosomes of mononuclear phagocyte system, attributable to acid beta-glucosidase deficiency. The main consequences of this disease are hepatosplenomegaly, skeletal lesions and, sometimes, neurological manifestations. At sub-inhibitory concentrations, several competitive inhibitors act as chemical chaperones by inducing protein stabilization and increasing enzymatic activity. Here we tested two iminosugars (NB-DNJ and NN-DNJ) and four aminocyclitols with distinct degrees of lipophilicity as pharmacological chaperones for glucocerebrosidase (GBA). We report an increase in the activity of GBA using NN-DNJ, NB-DNJ and aminocyclitol 1 in stably transfected cell lines, and an increment with NN-DNJ and aminocyclitol 4 in patient fibroblasts. These results on specific mutations validate the use of chemical chaperones as a therapeutic approach for Gaucher disease. However, the development and analysis of new compounds is required in order to find more effective therapeutic agents that are active on a broader range of mutations.

Molecular analysis in two beta-mannosidosis patients: description of a new adult case.

beta-Mannosidosis is a lysosomal storage disorder caused by deficiency of beta-mannosidase. Thirteen families with cases of beta-mannosidosis have been described including one case previously reported by our group. We present clinical and biochemical data in a new adult case, and the molecular analyses in both this new case and the one previously reported. We detected four novel mutations: p.R182W, p.G392E, p.W466X and c.1848delA. Discrepancies between genomic DNA and cDNA results when detecting this last deletion suggested a nonsense-mediated decay cell process (NMD).