TY - JOUR
T1 - Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex
AU - Lukong, Kiven E.
AU - Elsliger, Marc André
AU - Chang, Yuan
AU - Richard, Catherine
AU - Thomas, George
AU - Carey, William
AU - Tylki-Szymanska, Anna
AU - Czartoryska, Barbara
AU - Buchholz, Tina
AU - Criado, German Rodríguez
AU - Palmeri, Silvia
AU - Pshezhetsky, Alexey V.
PY - 2000/4/12
Y1 - 2000/4/12
N2 - 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 β-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.
AB - 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 β-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.
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U2 - 10.1093/hmg/9.7.1075
DO - 10.1093/hmg/9.7.1075
M3 - Article
C2 - 10767332
AN - SCOPUS:0034639933
SN - 0964-6906
VL - 9
SP - 1075
EP - 1085
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
ER -