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J. Biol. Chem., Vol. 276, Issue 20, 17286-17290, May 18, 2001
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From the 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
Mutations in Sialidosis Impair Sialidase Binding to the Lysosomal
Multienzyme Complex*
,,§,,
Service de Génétique
Médicale, Hôpital Sainte-Justine and Département de
Pédiatrie, Faculté de Médicine, Université de
Montréal, Montréal, Québec H3T 1C5, Canada and the
¶ Department of Anatomy and Cell Biology, McGill
University, Montréal, Québec H3A 2B2, Canada
-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.
*
This work was supported by operating grants from Canadian
Institutes of Health Research (FRN-15079), Fonds de La Recherche en
Santé du Québec, and Vaincre les Maladies Lysosomales
Foundation (France) to (A.V.P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Service de
génétique médicale Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montréal, Quebec H3T 1C5, Canada. Tel.:
514-345-4931/2736; Fax: 514-345-4801; E-mail:
alex@justine.umontreal.ca.
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