Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GM1-gangliosidosis and Morquio B disease are lysosomal storage disorders caused by beta-galactosidase deficiency attributable to mutations in the GLB1 gene. On reaching the endosomal-lysosomal compartment, the beta-galactosidase protein associates with the protective protein/cathepsin A (PPCA) and neuraminidase proteins to form the lysosomal multienzyme complex (LMC). The correct interaction of these proteins in the complex is essential for their activity. More than 100 mutations have been described in GM1-gangliosidosis and Morquio B patients, but few have been further characterized. We expressed 12 mutations suspected to be pathogenic, one known polymorphic change (p.S532G), and a variant described as either a pathogenic or a polymorphic change (p.R521C). Ten of them had not been expressed before. The expression analysis confirmed the pathogenicity of the 12 mutations, whereas the relatively high activity of p.S532G is consistent with its definition as a polymorphism. The results for p.R521C suggest that this change is a low-penetrant disease-causing allele. Furthermore, the effect of these beta-galactosidase changes on the LMC was also studied by coimmunoprecipitations and Western blotting. The alteration of neuraminidase and PPCA patterns in several of the Western blotting analyses performed on patient protein extracts indicated that the LMC is affected in at least some GM1-gangliosidosis and Morquio B patients.
...
PMID:Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients. 1766 28

A 37-year-old woman presented for routine obstetrical care at 15 weeks' gestational age and the fetus was found to have hydrops fetalis. Following elective termination of the pregnancy at 18 weeks' gestational age, pathologic examination of the female conceptus revealed findings suggestive of a lysosomal storage disease within the liver and cardiac muscle. Enzyme assays for beta-galactosidase, neuraminidase, alpha-l-iduronidase, beta-glucuronidase, beta-glucosidase, Morquio disease type A enzyme, beta-fucosidase, alpha-mannosidase, and beta-mannosidase were all normal, ruling out many of the common storage diseases. Electron microscopy identified vacuoles within hepatocytes, Kupffer cells, and cardiac myocytes resembling the autophagic vacuoles characteristic of a group of diseases known as the autophagic vacuolar myopathies (AVMs). Because these diseases are exceptionally rare in females, and because such autophagic vacuoles have never before been described in liver, we propose a novel entity of "AVM-like lysosomal storage disease" presenting as nonimmune hydrops in a female fetus.
...
PMID:An autophagic vacuolar myopathy-like disorder presenting as nonimmune hydrops in a female fetus. 1924 13

Allelic mutations of the lysosomal beta-galactosidase gene cause heterogeneous clinical phenotypes, such as GM1 gangliosidosis and Morquio B disease, the former being further classified into three variants, namely infantile, juvenile and adult forms; and heterogeneous biochemical phenotypes were shown in these forms. We tried to elucidate the bases of these diseases from a structural viewpoint. We first constructed a three-dimensional structural model of human beta-galactosidase by means of homology modeling. The human beta-galactosidase consists of three domains, such as, a TIM barrel fold domain, which functions as a catalytic domain, and two galactose-binding domain-like fold domains. We then constructed structural models of representative mutant beta-galactosidase proteins (G123R, R201C, I51T and Y83H) and predicted the structural change associated with each phenotype by calculating the number of affected atoms, determining the root-mean-square deviation and the solvent-accessible surface area, and by color imaging. The results show that there is a good correlation between the structural changes caused by amino-acid substitutions in the beta-galactosidase molecule, as well as biochemical and clinical phenotypes in these representative cases. Protein structural study is useful for elucidating the bases of these diseases.
...
PMID:Structural bases of GM1 gangliosidosis and Morquio B disease. 1964 15

G(M1)-gangliosidosis (GM1) and Morquio B disease (MBD) are rare lysosomal storage disorders caused by mutations in the gene GLB1. Its main gene product, human acid beta-galactosidase (beta-Gal) degrades two functionally important molecules, G(M1)-ganglioside and keratan sulfate in brain and connective tissues, respectively. While GM1 is a severe, phenotypically heterogenous neurodegenerative disorder, MBD is a systemic bone disease without effects on the central nervous system. A MBD-specific mutation, p.W273L, was shown to produce stable beta-Gal precursors, normally transported and processed to mature, intralysosomal beta-Gal. In accordance with the MBD phenotype, elevated residual activity against G(M1)-ganglioside, but strongly reduced affinity towards keratan sulfate was found. Most GM1 alleles, in contrast, were shown to affect precursor stability and intracellular transport. Specific alleles, p.R201C and p.R201H result in misfolded, unstable precursor proteins rapidly degraded by endoplasmic reticulum-associated protein degradation (ERAD). They may therefore be sensitive to stabilization by small molecules which bind at the active site and provide proper conformation. Thus the stabilized protein may escape from ERAD processes, and reach the lysosomes in an active state, as proposed for enzyme enhancement therapy (EET). This paper demonstrates that a novel iminosugar, DLHex-DGJ, has potent effects as competitive inhibitor of human acid beta-galactosidase in vitro, and describes its effects on activity, protein expression, maturation and intracellular transport in vivo in 13 fibroblasts lines with GLB1 mutations. Beside p.R201C and p.R201H, two further alleles, p.C230R and p.G438E, displayed significant sensitivity against DLHex-DGJ, with an increase of catalytic activity, and a normalization of transport and lysosomal processing of beta-Gal precursors.
...
PMID:DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts. 2040 38

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.
...
PMID:GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. 2149 94

Morquio B disease (MBD) or Mucopolysaccharidosis type IV B (MPS IV B) is caused by particular GLB1 mutations specifically affecting the affinity of beta-galactosidase to keratan sulphate, resulting in dysostosis multiplex resembling Morquio A (MPS IV A) disease (GALNS deficiency). Additional neuronopathic features of GM1 II/III (juvenile/adult) gangliosidosis have been reported in some patients. Our patient/caregiver online survey was aimed at elucidating the clinical manifestations of this ultra-rare condition. Comparing to previously published data on MPS IV A, the 30 respondents in our MBD group presented with greater growth chart values (weight and height) and with lesser effects of odontoid hypoplasia. The most common concerns are: (1) mobility issues - 84% having difficulty walking; (2) chronic pain - 96%; (3) surgeries - average 3 per person, 80% for hip problems; (4) hip dysplasia, knee/ankle concerns, and scoliosis. Approximately 50% of MBD participants live independently and actively contributing to society. Evidence from our survey results supports the notion that skeletal manifestations in MBD are milder than in the majority of patients with MPS IV A. The data collected will help with the establishment of clinically meaningful outcomes for future therapeutic trials, and with the counseling of newly diagnosed patients about their health expectations.
...
PMID:Morquio B patient/caregiver survey: First insight into the natural course of a rare GLB1 related condition. 3009 86


<< Previous 1 2 3 4 5 6

---