Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal
sialidase, which catalyzes the catabolism of sialoglycoconjugates. The disease is associated with progressive impaired vision, macular cherry-red spots, and
myoclonus (
sialidosis type I) or with skeletal dysplasia, Hurler-like phenotype,
dysostosis multiplex,
mental retardation, and hepatosplenomegaly (
sialidosis type II). We analyzed the effect of the missense mutations G68V, S182G, G227R, F260Y, L270F, A298V, G328S, and L363P, which are identified in the
sialidosis type I and
sialidosis type II patients, on the activity, stability, and intracellular distribution of
sialidase. We found that three mutations, F260Y, L270F, and A298V, which are clustered in the same region on the surface of the
sialidase molecule, dramatically reduced the
enzyme activity and caused a rapid intralysosomal degradation of the expressed
protein. We suggested that this region might be involved in
sialidase binding with lysosomal
cathepsin A and/or
beta-galactosidase in the multienzyme lysosomal complex required for the expression of
sialidase activity. Transgenic expression of mutants followed by density gradient centrifugation of cellular extracts confirmed this hypothesis and showed that
sialidase deficiency in some
sialidosis patients results from disruption of the lysosomal multienzyme complex.