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Human Molecular Genetics, 2000, Vol. 9, No. 7 1075-1085
© 2000 Oxford University Press

Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex

Kiven E. Lukong, Marc-André Elsliger+, Yuan Chang, Catherine Richard, George Thomas1, William Carey2, Anna Tylki-Szymanska3, Barbara Czartoryska4, Tina Buchholz5, German Rodríguez Criado6, Silvia Palmeri7 and Alexey V. Pshezhetsky§

Service de Génétique Médicale, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine and Département de Pédiatrie, Faculté de Médicine, Université de Montréal, Montréal, Quebec H3T 1C5, Canada, 1John Hopkins University School of Medicine, USA, 2Women’s and Children’s Hospital, North Adelaide, Australia, 3Metabolic Diseases Department, Child Health Center, Warsaw, Poland, 4Institute of Psychiatry and Neurology, Warsaw, Poland, 5Klinikum Grosshadern, Munich, Germany, 6Unidad de Dismorfología, Hospital Virgen del Rocío, Sevilla, Spain and 7Institute of Neurological Sciences, University of Siena, Italy

Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal sialidase, which catalyzes the hydrolysis 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 have analyzed the genomic DNA from nine sialidosis patients of multiple ethnic origin in order to find mutations responsible for the enzyme deficiency. The activity of the identified variants was studied by transgenic expression. One patient had a frameshift mutation (G623delG deletion), which introduced a stop codon, truncating 113 amino acids. All others had missense mutations: G679G->A (Gly227Arg), C893C->T (Ala298Val), G203G->T (Gly68Val), A544A->G (Ser182Gly) C808C->T (Leu270Phe) and G982G->A (Gly328Ser). We have modeled the three-dimensional structure of sialidase based on the atomic coordinates of the homologous bacterial sialidases, located the positions of mutations and estimated their potential effect. This analysis showed that five mutations are clustered in one region on the surface of the sialidase molecule. These mutations dramatically reduce the enzyme activity and cause a rapid intralysosomal degradation of the expressed protein. We hypothesize that this region may be involved in the interface of sialidase binding with lysosomal cathepsin A and/or ß-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.

+ Present address: The Scripps Research Institute, La Jolla, CA 92037, USA

§ To whom correspondence should be addressed. Tel: +1 514 345 4931/2736; Fax: +1 514 345 4801; Email: alex@justine.umontreal.ca


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