title: GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid beta-galactosidase.
abstract: Alterations in GLB1, the gene coding for acid beta-D-galactosidase (beta-Gal), can result in GM1 gangliosidosis (GM1), a neurodegenerative disorder, or in Morquio B disease (MBD), a phenotype with dysostosis multiplex and normal central nervous system (CNS) function. While most MBD patients carry a common allele, c.817TG>CT (p.W273L), only few of the >100 mutations known in GM1 can be related to a certain phenotype. In 25 multiethnic patients with GM1 or MBD, 11 missense mutations were found as well as one novel insertion and a transversion causing aberrant gene products. Except c.602G>A (p.R201H) and two novel alleles, c.592G>T (p.D198Y) and c.1189C>G (p.P397A), all mutants resulted in significantly reduced beta-Gal activities (<10% of normal) upon expression in COS-1 cells. Although c.997T>C (p.Y333H) expressed 3% of normal activity, the mutant protein was localized in the lysosomal-endosomal compartment. A homozygous case presented with late infantile GM1, while a heterozygous, juvenile case carried p.Y333H together with p.R201H. This allele, recently found in homozygous MBD, gives rise to rough endoplasmic reticulum (RER)-located beta-Gal precursors. Thus, unlike classical MBD, the phenotype of heterozygotes carrying p.R201H may rather be determined by poorly active, properly transported products of the counter allele than by the mislocalized p.R201H precursors.
authors.affiliation: Department of Paediatrics, Medical University of Graz, Graz A-8036, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Hofer
authors.forename: Karl
authors.initials: K
authors.lastname: Paul
authors.forename: Katrin
authors.initials: K
authors.lastname: Fantur
authors.forename: Michael
authors.initials: M
authors.lastname: Beck
authors.forename: Friederike
authors.initials: F
authors.lastname: Bürger
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
authors.forename: Ksenija
authors.initials: K
authors.lastname: Fumic
authors.forename: Jana
authors.initials: J
authors.lastname: Ledvinova
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lugowska
authors.forename: Helen
authors.initials: H
authors.lastname: Michelakakis
authors.forename: Briguita
authors.initials: B
authors.lastname: Radeva
authors.forename: Uma
authors.initials: U
authors.lastname: Ramaswami
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Eduard
authors.initials: E
authors.lastname: Paschke
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D020134:Catalytic Domain; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004591:Electrophoresis, Polyacrylamide Gel; D016537:Gangliosidosis, GM1 / Q000235:genetics*; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007223:Infant; D009085:Mucopolysaccharidosis IV / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D001616:beta-Galactosidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C061901:GLB1 protein, human; D001616:beta-Galactosidase