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Molecular pathology of NEU1 gene in sialidosis
Author(s) -
Seyrantepe Volkan,
Poupetova Helena,
Froissart Roseline,
Zabot MarieThérèse,
Maire Irène,
Pshezhetsky Alexey V.
Publication year - 2003
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10268
Subject(s) - biology , sialidase , missense mutation , mucolipidosis , nonsense mutation , phenotype , genetics , gene , neuraminidase , biochemistry , enzyme , virus
Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late‐onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry‐red macular spots, ataxia, hyperreflexia, and seizures. The severe early‐onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler‐like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme. Hum Mutat 22:343–352, 2003. © 2003 Wiley‐Liss, Inc.