Human Molecular Genetics, Vol 7, 313-321, Copyright © 1998 by Oxford University Press
RJ Rottier, E Bonten and A d'Azzo
Lysosomal neuraminidase (sialidase) occurs in a high molecular weight
complex with the glycosidase beta-galactosidase and the serine
carboxypeptidase protective protein/cathepsin A (PPCA). Association of the
enzyme with PPCA is crucial for its correct targeting and lysosomal
activation. In man two genetically distinct storage disorders are
associated with either a primary or a secondary deficiency of lysosomal
neuraminidase: sialidosis and galactosialidosis. In the mouse the naturally
occurring inbred strain SM/J presents with a number of phenotypic
abnormalities that have been attributed to reduced neuraminidase activity.
SM/J mice were originally characterized by their altered sialylation of
several lysosomal glycoproteins. This defect was linked to a single gene,
neu-1 , on chromosome 17, which was mapped by linkage analysis to the H-2
locus. In addition, these mice have an altered immune response that has
also been coupled to a deficiency of the Neu-1 neuraminidase. Here we
report the identification in SM/J mice of a single amino acid substitution
(L209I) in the Neu-1 protein which is responsible for the partial
deficiency of lysosomal neuraminidase. We propose that the reduced activity
is caused by the enzyme's altered affinity for its substrate, rather than a
change in substrate specificity or turnover rate. The mutant enzyme is
correctly compartmentalized in lysosomes and maintains the ability to
associate with its activating protein, PPCA. We propose that it is this
mutation that is responsible for the SM/J phenotype.
ARTICLES
A point mutation in the neu-1 locus causes the neuraminidase defect in the SM/J mouse
Department of Genetics, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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