g(m1)-ganglioside and Mucopolysaccharidosis-IV

Topics: G(M1) Ganglioside; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosidoses; Genetic Carrier Screening; Genetic Counseling; Glycoside Hydrolases; Humans; Leukodystrophy, Metachromatic; Lipidoses; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Phenotype; Polymorphism, Genetic

This study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).. Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.. The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the. This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

Topics: beta-Galactosidase; Female; G(M1) Ganglioside; Gangliosidosis, GM1; Humans; Mucopolysaccharidosis IV; Mutation; Pregnancy

G(M1) gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme β-d-galactosidase (β-Gal), which lead to accumulations of the β-Gal substrates, G(M1) ganglioside, and keratan sulfate. β-Gal is an exoglycosidase that catalyzes the hydrolysis of terminal β-linked galactose residues. This study shows the crystal structures of human β-Gal in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. Human β-Gal is composed of a catalytic TIM barrel domain followed by β-domain 1 and β-domain 2. To gain structural insight into the molecular defects of β-Gal in the above diseases, the disease-causing mutations were mapped onto the three-dimensional structure. Finally, the possible causes of the diseases are discussed.

Topics: 1-Deoxynojirimycin; beta-Galactosidase; Crystallography, X-Ray; G(M1) Ganglioside; Galactose; Gangliosidosis, GM1; Humans; Hydrolysis; Keratan Sulfate; Lysosomes; Models, Molecular; Mucopolysaccharidosis IV; Mutation; Protein Structure, Tertiary

The uptake and catabolism of [3H-ceramide]-GM1 was followed in living fibroblasts from patient with different forms of beta-galactosidase deficiency. Gangliosides are identified according to the nomenclature of Svennerholm (1963). A total inability to metabolize the ingested substrate was found in infantile GM1-gangliosidosis whereas cells from an adult GM1-gangliosidosis variant showed a slower rate of degradation, compared with controls. Morquio B fibroblasts had a comparable catabolism of GM1 as controls. Fibroblasts from different types of galactosialidosis, a recessive disease associated with a coexistent beta-galactosidase/neuraminidase deficiency all showed degradation of ingested GM1. In view of the molecular defect in this disease, this catabolism must be due to the 10-20% of monomeric beta-galactosidase molecules present in the lysosomes. Unexpectedly, in these cells an impaired metabolism of GM3 was found. The same finding was observed when cells with an isolated neuraminidase deficiency (mucolipidosis I) were loaded with GM1. A hypothesis is presented to explain these results.

Topics: Adult; beta-Galactosidase; Cells, Cultured; Fibroblasts; G(M1) Ganglioside; Galactosidases; Gangliosidoses; Humans; Infant; Mucolipidoses; Mucopolysaccharidosis IV

An improved method, which combined a number of published techniques, is described for the polyethylene-glycol-induced fusion of mononuclear human skin fibroblasts in the presence of phytohaemagglutinin-P and for the subsequent isolation of polynuclear cells by Ficoll gradient sedimentation. Enriched cultures contain between 60 and 75% multinucleated cells and may be maintained in culture without fetal calf serum for up to 14 days without significant overgrowth by the few contaminating mononuclear parental cells. Complementation appears not to occur between GM1 gangliosidosis and mucopolysaccharidosis, type VI B (Morquio) cell strains; this experimental observation provides support for the earlier hypothesis that the mutations for these conditions are allelic. Earlier observations that complementation does not occur between selected phenotypic variants (viz., neuronopathic forms and those without neurological involvement) of sphingomyelin storage (Niemann-Pick) disease or Gaucher's disease are confirmed.

Topics: Cell Fusion; Cells, Cultured; Enzymes; Fibroblasts; G(M1) Ganglioside; Gangliosidoses; Gaucher Disease; Genetic Complementation Test; Humans; Lysosomes; Mucopolysaccharidosis IV; Niemann-Pick Diseases

The nature of the molecular defect resulting in the beta-galactosidase deficiency in different forms of GM1-gangliosidosis and mucopolysaccharidosis IV B (Morquio B syndrome) was investigated. Normal and mutant cultured skin fibroblasts were labeled in vivo with [3H]leucine and immunoprecipitation studies with human anti-beta-galactosidase antiserum were performed, followed by polyacrylamide gel electrophoresis and fluorography. In Morquio B syndrome, the mutation does not interfere with the normal processing and intralysosomal aggregation of beta-galactosidase. In cells from infantile and adult GM1-gangliosidosis, 85-kDa precursor beta-galactosidase was found to be synthesized normally but more than 90% of the enzyme was subsequently degraded at one of the early steps in posttranslational processing. The residual 5-10% beta-galactosidase activity in adult GM1-gangliosidosis is 64-kDa mature lysosomal enzyme with normal catalytic properties but with a reduced ability of the monomeric form to aggregate into high molecular weight multimers. Knowledge of the exact nature of the molecular defect underlying beta-galactosidase deficiency in man may lead to a better understanding of the clinical and pathological heterogeneity among patients with different types of GM1-gangliosidosis and Morquio B syndrome.

Topics: beta-Galactosidase; Fibroblasts; G(M1) Ganglioside; Galactosidases; Gangliosidoses; Humans; Lysosomes; Mucopolysaccharidosis IV; Mutation; Skin