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

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Query: EC:3.1.6.12 (chondroitinase)
2,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sulfatase deficiency (MSD) is an inherited lysosomal storage disease characterized by the deficiency of at least seven sulfatases. The basic defect in MSD is thought to be in a post-translational modification common to all sulfatases. In accordance with this concept, RNAs of normal size and amount were detected in MSD fibroblasts for three sulfatases tested. cDNAs encoding arylsulfatase A, arylsulfatase B, or steroid sulfatase were introduced into MSD fibroblasts and fibroblasts with a single sulfatase deficiency by retroviral gene transfer. Infected fibroblasts overexpressed the respective sulfatase polypeptides. While in single-sulfatase-deficiency fibroblasts a concomitant increase of sulfatase activities was observed, MSD fibroblasts expressed sulfatase polypeptides with a severely diminished catalytic activity. From these results we conclude that the mutation in MSD severely decreases the capacity of a co- or post-translational process that renders sulfatases enzymatically active or prevents their premature inactivation.
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PMID:Multiple sulfatase deficiency: catalytically inactive sulfatases are expressed from retrovirally introduced sulfatase cDNAs. 134 58

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy disease) results from the deficient activity of the lysosomal enzyme, arylsulfatase B (ASB; N-acetylgalactosamine-4-sulfatase E.C.3.1.6.1). The enzymatic defect leads to the accumulation of the glycosaminoglycan, dermatan sulfate, primarily in connective tissue and reticuloendothelial cell lysosomes. Although MPS VI patients have normal intelligence and no neurologic abnormalities, the disease is clinically heterogeneous: severely affected individuals expire in childhood or early adolescence while those with the mild or intermediate phenotypes have a slower, milder disease course and a longer life span. The recent isolation of the full-length cDNA-encoding human ASB permitted an investigation of the molecular lesions underlying the phenotypic heterogeneity in MPS VI. The ASB cDNA-coding sequences were determined from two unrelated MPS VI patients with the severe (proband 1) and mild (proband 2) phenotypes. These patients had about 2% and 7% of normal ASB activity in cultured fibroblasts, respectively. Proband 1 was homoallelic for a T-to-C transition in nucleotide (nt) 349, which predicted a cysteine-to-arginine substitution in the ASB polypeptide at residue 117 (C117R). Proband 2 was heteroallelic, having a T-to-C transition in nt 707, which predicted a leucine-to-proline replacement at ASB residue 236 (L236P), and having a G-to-A transition in nt 1214, which predicted a cysteine-to-tyrosine substitution at ASB residue 405 (C405Y). These mutations did not occur in three other unrelated MPS VI patients or in 120 ASB alleles from normal individuals, indicating that they were not polymorphisms. The identification of these three ASB mutations documents the first evidence of molecular heterogeneity in MPS VI and provides an initial basis for genotype/phenotype correlations in this lysosomal storage disease.
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PMID:Mucopolysaccharidosis type VI: identification of three mutations in the arylsulfatase B gene of patients with the severe and mild phenotypes provides molecular evidence for genetic heterogeneity. 155 Jan 23

The Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is a lysosomal storage disease with autosomal recessive inheritance caused by deficiency of the enzyme arylsulfatase B. Severe, intermediate, and mild forms of the disease have been described. The molecular correlate of the clinical heterogeneity is not known at present. To identify the molecular defect in a patient with the intermediate form of the disease, arylsulfatase B mRNA from his fibroblasts was reverse-transcribed, amplified by the polymerase chain reaction, and subcloned. Three point mutations were detected by DNA sequence analysis, two of which, a silent A to G transition at nucleotide 1191 and a G to A transition at nucleotide 1126 resulting in a methionine for valine 376 substitution, were polymorphisms. A G to T transversion at nucleotide 410 causing a valine for glycine 137 substitution (G137V) was identified as the mutation underlying the Maroteaux-Lamy phenotype of the patient, who was homozygous for the allele. The kinetic parameters of the mutant arylsulfatase B enzyme toward a radiolabeled trisaccharide substrate were normal excluding an alteration of the active site. The G137V mutation did not affect the synthesis but severely reduced the stability of the arylsulfatase B precursor. While the wild type precursor is converted by limited proteolysis in late endosomes or lysosomes to a mature form, the majority of the mutant precursor was degraded presumably in a compartment proximal to the trans Golgi network and only a small amount escaped to the lysosomes accounting for the low residual enzyme activity in fibroblasts of a patient with the juvenile form of the disease.
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PMID:Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). An intermediate clinical phenotype caused by substitution of valine for glycine at position 137 of arylsulfatase B. 171 78

Mucopolysaccharidosis type VI (MPSVI, Maroteaux-Lamy syndrome) is a lysosomal storage disease for which multiple clinical phenotypes have been described. A deficiency of the enzyme arylsulfatase B (ASB, N-acetylgalactosamine-4-sulfatase) is the cause of this autosomal recessively inherited disorder. The genotypes of two patients with an intermediate form of MPSVI have been determined by polymerase chain reaction (PCR) amplification of the entire open reading frame of the ASB gene and subsequent direct sequencing of both strands of the PCR fragments by an automated nonradioactive approach. In patient A, a C to T transition in allele I resulting in an exchange of the Arg codon 160 for a premature stop codon (R160*, exon 2), and a G to A transition in allele II leading to a Gln to Arg160 substitution (R160Q, exon 2) were detected. Patient B exhibited a 7-bp deletion in exon 1 of allele I resulting in a frame shift and a premature stop codon 33 triplets 3' of the site of deletion (delta G237-C243), and a C to T transition in allele II giving rise to a Trp to Arg152 substitution (R152W, exon 2). None of these four mutant alleles was present among 60 alleles of the ASB gene in unrelated controls, indicating that the former are not polymorphisms. These results emphasize the broad molecular heterogeneity of Maroteaux-Lamy syndrome and contribute to the establishment of a genotype/phenotype correlation in this disease.
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PMID:Four novel mutant alleles of the arylsulfatase B gene in two patients with intermediate form of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). 812 75

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase B (ASB), which is involved in degradation of dermatan sulfate and chondroitin 4-sulfate. A MPS VI mouse model was generated by targeted disruption of the ASB gene. Homozygous mutant animals exhibit ASB enzyme deficiency and elevated urinary secretion of dermatan sulfate. They develop progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age facial dysmorphia becomes overt, long bones are shortened, and pelvic and costal abnormalities are observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals are seen. All major parenchymal organs show storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice are fertile and mortality is not elevated up to 15 months of age. This mouse model will be a valuable tool for studying pathogenesis of MPS VI and may help to evaluate therapeutical approaches for lysosomal storage diseases.
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PMID:Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI. 871 Aug 49

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulfatase (4S). A feline MPS VI model used to demonstrate efficacy of enzyme replacement therapy is due to the homozygous presence of an L476P mutation in 4-sulfatase. An additional mutation, D520N, inherited independently from L476P and recently identified in the same family of cats, has resulted in three clinical phenotypes. L476P homozygotes exhibit dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormally low leukocyte 4S/betahexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues including chondrocytes, corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats have abnormally low leukocyte 4S/betahexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions. However, both have normal growth and appearance. In addition, L476P/D520N cats have a high incidence of degenerative joint disease. We conclude that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. The study of L476P/D520N and D520N/ D520N genotypes will improve understanding of genotype to phenotype correlations and the pathogenesis of skeletal dysplasia and joint disease in MPS VI, and will assist in development of therapies to prevent lysosomal storage in chondrocytes.
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PMID:Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes. 942 72

Mucopolysaccharidosis (MPS) Type VI (Maroteaux-Lamy Disease) is the lysosomal storage disease characterized by deficient arylsulfatase B activity and the resultant accumulation of dermatan sulfate-containing glycosaminoglycans (GAGs). A major feature of this and other MPS disorders is abnormal cartilage and bone development leading to short stature, dysostosis multiplex, and degenerative joint disease. To investigate the underlying cause(s) of degenerative joint disease in the MPS disorders, articular cartilage and cultured articular chondrocytes were examined from rats and cats with MPS VI. An age-progressive increase in the number of apoptotic chondrocytes was identified in the MPS animals by terminal transferase nick-end translation (TUNEL) staining and by immunohistochemical staining with anti-poly (ADP-ribose) polymerase (PARP) antibodies. Articular chondrocytes grown from these animals also released more nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) into the culture media than did control chondrocytes. Notably, dermatan sulfate, the GAG that accumulates in MPS VI cells, induced NO release from normal chondrocytes, suggesting that GAG accumulation was responsible, in part, for the enhanced cell death in the MPS cells. Coculture of normal chondrocytes with MPS VI cells reduced the amount of NO release, presumably because of the release of arylsulfatase B by the normal cells and reuptake by the mutant cells. As a result of the enhanced chondrocyte death, marked proteoglycan and collagen depletion was observed in the MPS articular cartilage matrix. These results demonstrate that MPS VI articular chondrocytes undergo cell death at a higher rate than normal cells, because of either increased levels of dermatan sulfate and/or the presence of inflammatory cytokines in the MPS joints. In turn, this leads to abnormal cartilage matrix homeostasis in the MPS individuals, which further exacerbates the joint deformities characteristic of these disorders.
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PMID:Articular chondrocytes from animals with a dermatan sulfate storage disease undergo a high rate of apoptosis and release nitric oxide and inflammatory cytokines: a possible mechanism underlying degenerative joint disease in the mucopolysaccharidoses. 1155 79

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulphatase (arylsulfatase B, ASB). We report the clinical investigation and mutation analysis of two Taiwanese patients with severe (Case 1) and intermediate (Case 2) phenotypes of MPS VI. Three missense mutations and one polymorphism were identified. Case 1 was found to have a novel heteroallelic C-to-G transversion at nucleotide 1197 causing a phenylalanine to leucine substitution at residue 399 (Phe399Leu), and a heteroallelic Gln239Arg mutation. In Case 2, a heterozygous Cys192Arg mutation and a Val358Met polymorphism were identified. Among these three mutations, the Gln239Arg and Phe399Leu substitutions have so far been observed only in the Taiwanese population. The correlation between genotype and phenotype contributes to molecular pre- and post-natal diagnosis for MPS VI patients.
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PMID:Mucopolysaccharidosis type VI: Report of two Taiwanese patients and identification of one novel mutation. 1180 22

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of arylsulfatase B (ASB) which has its function in the sequential degradation of glycosaminoglycans (GAG). Targeted disruption of the ASB gene resulted in a mouse model of MPS VI that has been closely investigated for skeletal and chondral dysplasia. As ocular and cardiac impairment are also clinically important manifestations of the MPS VI syndrome, the present study was initiated for detailed biochemical, histologic and functional analysis of cornea, optic nerve and heart in ASB-deficient mice. Biochemical evidence for GAG-storage could be obtained for liver, kidney, spleen and myocardium as well as for heart valves, cornea and optic nerve from ASB-deficient mice. In MPS VI mice, histology revealed structural impairment of corneal stroma and epithelium as well as a thickening of the heart valves. According to histologic investigations, the optic nerve appeared not to be altered. However, GAG-storage in the dura mater could be demonstrated in MPS VI mice. Heart function was assessed by echocardiography. While the dimensions of MPS VI hearts were not altered, these hearts clearly showed decreased myocardial contraction and a 50% reduction of cardiac output. In addition, insufficiencies in the mitral and aortic valves were detected. Thus, ASB-deficient mice resemble the phenotype of human MPS VI not only in the skeletal but also in the ocular and cardiac symptoms. To our knowledge, these in vivo evaluations of heart function represent the first respective investigation of a MPS VI animal model and should provide a valuable measure for therapy studies in the MPS VI mouse.
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PMID:Cardiac and ocular pathologies in a mouse model of mucopolysaccharidosis type VI. 1290 6

MPS VI (mucopolysaccharidosis type VI) is a lysosomal storage disease in which deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase [ASB (arylsulfatase B)] impairs the stepwise degradation of the GAG (glycosaminoglycan) dermatan sulfate. Clinical studies of ERT (enzyme replacement therapy) by using rhASB (recombinant human ASB) have been reported with promising results. The release of GAG into the urine is currently used as a biomarker of disease, reflecting in some cases disease severity and in all cases therapeutic responsiveness. Using RNA studies in four Italian patients undergoing ERT, we observed that TNFalpha (tumour necrosis factor alpha) might be a biomarker for MPS VI responsive to therapy. In addition to its role as a potential biomarker, TNFalpha expression could provide insights into the possible pathophysiological mechanisms underlying the mucopolysaccharidoses.
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PMID:Molecular markers for the follow-up of enzyme-replacement therapy in mucopolysaccharidosis type VI disease. 1767 28


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