title: Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations.
abstract: GM1 gangliosidosis manifests with progressive psychomotor deterioration and dysostosis of infantile, juvenile, or adult onset, caused by alterations in the structural gene coding for lysosomal acid beta-galactosidase (GLB1). In addition, allelic variants of this gene can result in Morquio B disease (MBD), a phenotype with dysostosis multiplex and entire lack of neurologic involvement. More than 100 sequence alterations in the GLB1 gene have been identified so far, but only few could be proven to be predictive for one of the GM1 gangliosidosis subtypes or MBD. We performed genotype analyses in 16 GM1 gangliosidosis patients of all phenotypes and detected 28 different genetic lesions. Among these, p.I55FfsX16, p.W65X, p.F107L, p.H112P, p.C127Y, p.W161X, p.I181K, p.C230R, p.W273X, p.R299VfsX5, p.A301V, p.F357L, p.K359KfsX23, p.L389P, p.D448V, p.D448GfsX8, and the intronic mutation IVS6-8A>G have not been published so far. Due to their occurrence in homozygous patients, four mutations could be correlated to a distinct GM1 gangliosidosis phenotype. Furthermore, the missense mutations from heteroallelic patients and three artificial nonsense mutations were characterized by overexpression in COS-1 cells, and the subcellular localization of the mutant proteins in fibroblasts was assessed. The phenotype specificity of 10 alleles can be proposed on the basis of our results and previous data.
authors.affiliation: Department of Paediatrics, Medical University of Graz, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Hofer
authors.forename: K
authors.initials: K
authors.lastname: Paul
authors.forename: K
authors.initials: K
authors.lastname: Fantur
authors.forename: M
authors.initials: M
authors.lastname: Beck
authors.forename: A
authors.initials: A
authors.lastname: Roubergue
authors.forename: A
authors.initials: A
authors.lastname: Vellodi
authors.forename: B J
authors.initials: BJ
authors.lastname: Poorthuis
authors.forename: H
authors.initials: H
authors.lastname: Michelakakis
authors.forename: B
authors.initials: B
authors.lastname: Plecko
authors.forename: E
authors.initials: E
authors.lastname: Paschke
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D016537:Gangliosidosis, GM1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006801:Humans; D007223:Infant; D009154:Mutation; D010641:Phenotype; D001616:beta-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: C061901:GLB1 protein, human; D001616:beta-Galactosidase