Human Molecular Genetics, 2000, Vol. 9, No. 18 2715-2725
© 2000 Oxford University Press
Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis
1St Jude Children’s Research Hospital, Department of Genetics, 332 North Lauderdale, Memphis, TN 38105, USA, 2Sophia Children’s Hospital, Department of Pediatric Neurology, Dr Molewaterplein 60, NL-3015 GJ Rotterdam, The Netherlands, 3Children’s Hospital of the Johannes-Gutenberg University, Langenbeckstrasse 1, D-55131 Mainz, Germany, 4Aghia Sophia Children’s Hospital, Department of Neurology/Neurophysiology, E-115 27 Athens, Greece, 5Department of Pediatrics, Florence University, Meyer Children’s Hospital, Via Luca Giordano 13, I-50132 Firenze, Italy, 6Clinica Pediatrica II, Centro Malattie Metaboliche, Via Commenda 9, I-20122 Milano, Italy and 7University of Tennessee, Department of Anatomy and Neurobiology, 800 Madison Avenue, Memphis, TN 38163, USA
Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative lysosomal disorders, sialidosis and galactosialidosis. Here we report the identification of eight novel mutations in the neuraminidase gene of 11 sialidosis patients with various degrees of disease penetrance. Comparison of the primary structure of human neuraminidase with the primary and tertiary structures of bacterial sialidases indicated that most of the single amino acid substitutions occurred in functional motifs or conserved residues. On the basis of the subcellular distribution and residual catalytic activity of the mutant neuraminidases we assigned the mutant proteins to three groups: (i) catalytically inactive and not lysosomal; (ii) catalytically inactive, but 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 severe 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 patients with intermediate clinical severity. Overall, our findings explain the clinical heterogeneity observed in sialidosis and may help in the assignment of existing or new allelic combinations to specific phenotypes.
+ To whom correspondence should be addressed at: St Jude Children’s Research Hospital, Department of Genetics, 332 North Lauderdale, Memphis, TN 38105, USA. Tel: +1 901 495 2698; Fax: +1 901 526 2907; Email: alessandra.dazzo@stjude.org
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