Analysis Of Lysosomal Protective Protein Gene Mutations In Galactosialidosis And Its Structure-Function Relationship

Galactosialidosis is a lysosomal storage disorder caused by mutations in the gene encoding the protective protein/ cathepsin A. Lysosomal protective protein has two so far identified functions: a protective function for P -glactosidase and neuraminidase by couplexing with the two lysosomal enzymes and protecting them against excessive proteolytic degradation and Cathepsin A activity. The protective protein is synthesized as a 54 kDa precursor that is processed into two subunits of 32-and 20-kDa, held together by disulfide bridges. The primary structure of human protective protein is homologous to yeast and plant serine carboxypepetidase. It is structurally and functionally similar to lysosmal cathepsin A and to a platelet deamidase/carboxypeptidase that cleaves important bioactive peptides. The catalytic and protective functions of the protective protein appear to be distinct. Its deamidase/ carboxypeptidase activty has been found to be deficient in all patients with galactosialidosis so far studied.The aim of this thesis is to identify the underlying genetic abnormalities in the mutant alleles of the protective protein gene in galactosialidosis patients with differnt clinical phenotypes in order to allow a better understanding of this disease as well as the role of this potentially multifunctional protein, and to provide more insight into the structure-function relationship of the protective protein. We have identified different mutant alleles associated with the three clinical...