title: Molecular and structural studies of Japanese patients with sialidosis type 1.
abstract: To gain insight into the pathogenesis of sialidosis type 1, we performed molecular investigations of two unrelated Japanese patients. Both of them are compound heterozygotes for base substitutions of 649G-to-A and 727G-to-A, which result in amino acid alterations V217M and G243R, respectively. Using homology modeling, the structure of human lysosomal neuraminidase was constructed and the structural changes caused by these missense mutations were deduced. The predicted change due to V217M was smaller than that caused by G243R, the latter resulting in a drastic, widespread alteration. The overexpressed gene products containing these mutations had the same molecular weight as that of the wild type, although the amounts of the products were moderately decreased. A biochemical study demonstrated that the expressed neuraminidase containing a V217M mutation was partly transported to lysosomes and showed residual enzyme activity, although a G243R mutant was retained in the endoplasmic reticulum/Golgi area and had completely lost the enzyme activity. Considering the data, we surmise that the V217M substitution may be closely associated with the phenotype of sialidosis type 1 with a late onset and moderate clinical course.
authors.affiliation: Department of Clinical Genetics, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Naganawa
authors.forename: K
authors.initials: K
authors.lastname: Itoh
authors.forename: M
authors.initials: M
authors.lastname: Shimmoto
authors.forename: K
authors.initials: K
authors.lastname: Takiguchi
authors.forename: H
authors.initials: H
authors.lastname: Doi
authors.forename: Y
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Kamei
authors.forename: K E
authors.initials: KE
authors.lastname: Lukong
authors.forename: A V
authors.initials: AV
authors.lastname: Pshezhetsky
authors.forename: H
authors.initials: H
authors.lastname: Sakuraba
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008958:Models, Molecular; D009081:Mucolipidoses / Q000201:enzymology / Q000235:genetics*; D020125:Mutation, Missense; D009439:Neuraminidase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D017422:Sequence Analysis, DNA
chemical_list: D009439:Neuraminidase