Molecular defect in combined beta-galactosidase and neuraminidase deficiency in man.

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Abstract
In normal human fibroblasts, an enzymically active 85,000-dalton precursor form of .beta.-galactosidase is processed, via a number of intermediates, into a mature 64,000-dalton form. In addition there is an enzymically inactive 32,000-dalton component and its 54,000-dalton precursor. In fibroblasts from patients with a combined deficiency of .beta.-galactosidase and neuraminidase these last 2 components are absent and hardly any mature .beta.-galactosidase can be demonstrated. Nevertheless, in the mutant fibroblasts, precursor .beta.-galactosidase is synthesized and processed normally. The excessive intralysosomal degradation that is responsible for the deficiency of mature .beta.-galactosidase can be partially corrected by addition of the protease inhibitor leupeptin, which results in the accumulation of 85,000-dalton precursor .beta.-galactosidase and of a partially processed 66,00-dalton form. When mutant cells were grown in the presence of a corrective factor purified from the medium of NH4Cl-stimulated cell cultures, both .beta.-galactosidase and neuraminidase activities were restored to low control levels. The immunoprecipitation pattern was completely normal after addition of the corrective factor, and mature 64,000-dalton .beta.-galactosidase accumulated in the mutant fibroblasts. The combined .beta.-galactosidase/neuraminidase deficiency is probably caused by a defective 32,000-dalton glycoprotein which is normally required to protect .beta.-galactosidase and neuraminidase against excessive intralysosomal degradation and to give these enzymes their full hydrolytic activity.