title: Molecular pathology of galactosialidosis in a patient affected with two new frameshift mutations in the cathepsin A/protective protein gene.
abstract: Galactosialidosis is a recessively inherited lysosomal storage disease characterized by the combined deficiency of neuraminidase and beta-galactosidase secondary to the genetic deficiency of cathepsin A/protective protein. In lysosomes, cathepsin A forms a high-molecular-weight complex with beta-galactosidase and neuraminidase that protects these enzymes against intralysosomal proteolysis. In a patient affected with late infantile form of galactosialidosis, we found two new cathepsin A mutations, a two-nucleotide deletion, c517delTT and an intronic mutation, IVS8+9C-->G resulting in abnormal splicing and a five-nucleotide insertion in the cathepsin A cDNA. Both mutations cause frameshifts and result in the synthesis of truncated cathepsin A proteins, which, as suggested by structural modeling, are incapable of dimerization, complex formation, and catalysis. However, enzymatic assays, gel-filtration, and Western blot analysis of the patient's cultured skin fibroblast extracts showed the presence of a small amount of normal-size, catalytically active cathepsin A and cathepsin A-beta-galactosidase 680 kDa complex, suggesting that a low amount of cathepsin A mRNA is spliced normally and produces the wild-type protein. This may contribute to the relatively mild phenotype of the patient and illustrates the importance of critically comparing molecular results with clinical and biochemical phenotypes.
authors.affiliation: Hôpital Sainte-Justine, Département de Pédiatrie, Faculté de Médecine, Université de Montréal, Québec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Richard
authors.forename: J
authors.initials: J
authors.lastname: Tranchemontagne
authors.forename: M A
authors.initials: MA
authors.lastname: Elsliger
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: M
authors.initials: M
authors.lastname: Potier
authors.forename: A V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002268:Carboxypeptidases / Q000172:deficiency / Q000235:genetics*; D043402:Cathepsin A; D002478:Cells, Cultured; D017931:DNA Primers; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009439:Neuraminidase / Q000172:deficiency; D009692:Nucleic Acid Heteroduplexes; D012326:RNA Splicing; D001616:beta-Galactosidase / Q000172:deficiency
chemical_list: D017931:DNA Primers; D009692:Nucleic Acid Heteroduplexes; D009439:Neuraminidase; D001616:beta-Galactosidase; D002268:Carboxypeptidases; C468629:CTSA protein, human; D043402:Cathepsin A