title: GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings.
abstract: GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes showed that all the amino acid replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease.
authors.affiliation: Metabolic and Muscular Unit, Clinic of Pediatric Neurology, Meyer Children's Hospital, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.forename: Scott C
authors.initials: SC
authors.lastname: Garman
authors.forename: Yadilette
authors.initials: Y
authors.lastname: Rivera-Colón
authors.forename: Elena
authors.initials: E
authors.lastname: Procopio
authors.forename: Serena
authors.initials: S
authors.lastname: Catarzi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferri
authors.forename: Carmen
authors.initials: C
authors.lastname: Guido
authors.forename: Paola
authors.initials: P
authors.lastname: Martelli
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.forename: Daniela
authors.initials: D
authors.lastname: Antuzzi
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.forename: Michela
authors.initials: M
authors.lastname: Sibilio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Simonati
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.forename: Alessandro
authors.initials: A
authors.lastname: Salviati
authors.forename: Gulcin
authors.initials: G
authors.lastname: Akinci
authors.forename: Cristina
authors.initials: C
authors.lastname: Cereda
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Francesca
authors.initials: F
authors.lastname: Deodato
authors.forename: Adele
authors.initials: A
authors.lastname: d'Amico
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scarpa
authors.forename: Maja
authors.initials: M
authors.lastname: di Rocco
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.forename: Federica
authors.initials: F
authors.lastname: Ciani
authors.forename: Serena
authors.initials: S
authors.lastname: Gasperini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pasquini
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D005260:Female; D016537:Gangliosidosis, GM1 / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D007223:Infant; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009085:Mucopolysaccharidosis IV / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D001616:beta-Galactosidase / Q000737:chemistry / Q000235:genetics
chemical_list: C061901:GLB1 protein, human; D001616:beta-Galactosidase