Molecular and structural studies of Japanese patients with sialidosis type1

To gain insight into the pathogenesis of sialidosis type 1, we performed mo lecular investigations of two unrelated Japanese patients, Both of them are compound heterozygotes for base substitutions of (649)G-to-A and (727)G-to -A, which result in amino acid alterations V217M and G243R, respectively. U sing homology modeling, the structure of human lysosomal neuraminidase was constructed and the structural changes caused by these missense mutations w ere deduced. The predicted change due to V217M was smaller than that caused by G243R, the latter resulting in a drastic, widespread alteration. The ov erexpressed 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 lysosom es and showed residual enzyme activity, although a G243R mutant was retaine d in the endoplasmic reticulum/Golgi area and had completely lost the enzym e activity. Considering the data, we surmise that the V217M substitution ma y be closely associated with the phenotype of sialidosis type 1 with a late onset and moderate clinical course.