Characterization of beta-galactosidase mutations Asp332-->Asn and Arg148-->Ser, and a polymorphism, Ser532-->Gly, in a case of GM1 gangliosidosis.

We have identified and characterized three missense mutations in a patient with type 1 G(M1) gangliosidosis, namely a substitution of G for A at nucleotide position 1044 (G1044-->A; in exon 10) on one allele, which converts Asp(332) into asparagine, and both a mutation (C492-->A in exon 4, leading to the amino acid change of Arg(148)-->Ser) and a polymorphism (A1644-->G in exon 15, leading to a change of Ser(532)-->Gly) on the other allele. This patient had less than 1% residual beta-galactosidase activity and minimally detectable levels of immunoreactive beta-galactosidase protein in fibroblasts. To account for the above findings, a series of expression and immunolocalization studies were undertaken to assess the impact of each mutation.

Early proteolytic cleavage with loss of a C-terminal fragment underlies altered processing of the beta-galactosidase precursor in galactosialidosis.

Processing of human beta-galactosidase (beta-GAL) was studied in permanently transfected Chinese hamster ovary (CHO) cells and compared with that in normal cells and in cells from subjects with GM1-gangliosidosis, galactosialidosis and I-cell disease. Biosynthesis of beta-GAL in CHO cells results in the synthesis of an 88 kDa glycosylated and phosphorylated monomer precursor which is enzymically active and is secreted into the medium. Post-translational processing begins at the C-terminal end of the protein and gives rise to structurally related 67 and 64 kDa mature forms.

Homozygous presence of the crossover (fusion gene) mutation identified in a type II Gaucher disease fetus: is this analogous to the Gaucher knock-out mouse model?

Gaucher disease (GD) is an inherited deficiency of beta-glucocerebrosidase (EC 3.1.2.