Novel mutations in lysosomal neuraminidase identify functional domains anddetermine clinical severity in sialidosis

Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative ly sosomal disorders, sialidosis and galactosialidosis. Here we report the ide ntification of eight novel mutations in the neuraminidase gene of 11 sialid osis patients with various degrees of disease penetrance. Comparison of the primary structure of human neuraminidase with the primary and tertiary str uctures of bacterial sialidases indicated that most of the single amino aci d substitutions occurred in functional motifs or conserved residues. On the basis of the subcellular distribution and residual catalytic activity of t he mutant neuraminidases we assigned the mutant proteins to three groups: ( i) catalytically inactive and not lysosomal; (ii) catalytically inactive, b ut localized in lysosome; and (iii) catalytically active and lysosomal. In general, there was a close correlation between the residual activity of the mutant enzymes and the clinical severity of disease. Patients with the sev ere infantile type II disease had mutations from group I, whereas patients with a mild form of type I disease had at least one mutation from group III . Mutations from the second group were mainly found in juvenile type II pat ients with intermediate clinical severity. Overall, our findings explain th e clinical heterogeneity observed in sialidosis and may help in the assignm ent of existing or new allelic combinations to specific phenotypes.