Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.6.4 (chondroitinase)
 2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of the lysosomal enzyme, N-acetylgalactosamine 6-sulfatase (GALNS;EC 3.1.6.4), results in the storage of the glycosaminoglycans, keratan sulfate and chondroitin 6-sulfate, which leads to the lysosomal storage disorder Morquio A syndrome. Four overlapping genomic clones derived from a chromosome 16-specific gridded cosmid library containing the entire GALNS gene were isolated. The structure of the gene and the sequence of the exon/intron boundaries and the 5' promoter region were determined. The GALNS gene is split into 14 exons spanning approximately 40 kb. The potential promoter for GALNS lacks a TATA box but contains GC box consensus sequences, consistent with its role as a housekeeping gene. The GALNS gene contains an Alu repeat in intron 5 and a VNTR-like sequence in intron 6.
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PMID:Morquio A syndrome: cloning, sequence, and structure of the human N-acetylgalactosamine 6-sulfatase (GALNS) gene. 800 80

Mucopolysaccharidosis IV A (MPS IV A) is the result of a genetic deficiency in a lysosomal hydrolase, N-acetylgalactosamine-6-sulfatase (GALNS). To investigate MPS IV A patients at the level of the genome, we analyzed the structure of the human GALNS-encoding gene. From the genomic library of a normal subject in lambda EMBL3, we isolated five overlapping clones covering the coding region of the GALNS cDNA and determined the structural organization. The gene is about 50 kb long and contains 14 exons. The 5'-flanking region lacks a canonical TATA box and CCAAT sequences, but is G+C-rich (70.5%), with four GC boxes, characteristic of a housekeeping gene promoter. The transcription initiation site was determined by primer extension analysis, using RNA from human liver and HeLa cells. Transcription was found to initiate at a few sites, the major ones being 58 and 22 bp upstream of the translation initiation codon. The 5'-flanking region had promoter activity by transient expression, determined using a CAT assay. In addition, this region retained promoter activity, even in reverse orientation. The region -98 to -1 upstream of the ATG codon was defined by deletion analysis to be a minimal promoter. One GC box in this region is likely to be a binding site of a regulatory element.
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PMID:Mucopolysaccharidosis IV A: molecular cloning of the human N-acetylgalactosamine-6-sulfatase gene (GALNS) and analysis of the 5'-flanking region. 802 Sep 61

The gene for N-acetylgalactosamine-6-sulfatase, the deficiency of which results in Morquio A syndrome (mucopolysaccharidosis type IVA), was assigned to chromosome 16 at band q24.3 by fluorescence in situ hybridization. Localization of this band was confirmed by PCR analysis of a somatic cell hybrid panel used for fine mapping of chromosome 16.
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PMID:The morquio A syndrome (mucopolysaccharidosis IVA) gene maps to 16q24.3. 843 12

Morquio syndrome (mucopolysaccharidosis IV) presents with multiple bone dysplasia and is characterized by the inability to degrade keratan sulfate due to deficient N-acetylgalactosamine-6-sulfate sulfatase in Morquio A syndrome and deficient beta-D-galactosidase in Morquio B syndrome. The aim of our study was to investigate into the pathogenetic mechanism as it is not clear whether the accumulation of keratan sulfate is toxic for osteoblasts or inhibits osteoblast activity as e.g. bone resorption. The glycosaminoglycans keratan sulfate, heparan sulfate, dermatan sulfate, chondroitin-4,6-sulfate and hyaluronic acid were tested in rat neonatal calvarian cultures for their effects on bone resorption, osteoblast activity and toxicity. Bone resorption was evaluated by calcium release into the medium, osteoblast activity by the determination of alkaline phosphatase and toxicity by measuring lactate dehydrogenase in the culture media. Keratan sulfate had no effect on bone resorption but inhibited osteoblast activity at the low, nontoxic concentration of 10 ng per ml organ culture supernatant significantly (p<0.05). At a concentration of 100 ng per ml keratan sulfate revealed toxic effects as reflected by significantly (p<0.05) elevated lactate dehydrogenase activity. None of the other glycosaminoglycans inhibited osteoblast activities. Heparan sulfate showed at toxic levels (10 microg per ml supernatant) significantly increased bone resorption (p<0.05) accompanied by increased alkaline phosphatase activity. The specific keratan sulfate effects of inhibiting osteoblast activity and toxicity towards bone, which were never tested before, suggest a role for this glycosaminoglycan in the pathogenesis of bone dysplasia in Morquio syndrome.
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PMID:The effects of acid glycosaminoglycans on neonatal calvarian cultures--a role of keratan sulfate in Morquio syndrome? 927 6

Mucopolysaccharidosis type IVA (Morquio A) is caused by a deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme capable of cleaving the sulfate group from both N-acetylgalactosamine-6-sulfate and galactose-6-sulfate. We describe here a two-generation Morquio A family with two distinct clinical phenotypes. The two probands from the second generation showed intermediate signs of the disease whereas their affected mother, aunt and two uncles had only very mild symptoms. Galactose-6-sulfatase (GALS) activity in leukocytes and fibroblasts of the affected family members was clearly deficient. Molecular genetic analysis of the GALNS gene revealed that two different point mutations segregate in the family, which correlated well with the clinical phenotype. The probands with intermediate symptoms were compound heterozygotes for the mutations R259Q and R94G, the latter one being inherited from the unaffected father. The mother and her affected siblings with the unusually mild phenotype were proven to be homozygous for the novel missense point mutation R259Q.
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PMID:Clinical, biochemical and molecular findings in a two-generation Morquio A family. 966 54

Deficiency of lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS) leads to mucopolysaccharidosis IV A (MPS IV A), for which there is no definitive treatment so far. Although a number of mutations of the GALNS gene of MPS IV A patients have been described, pathogenesis of the disorder still remains elusive. In order to facilitate in vivo studies using model animals for MPS IV A, we isolated and performed molecular characterization of the mouse homolog of human GALNS. The 2.3-kb cDNA contains a 1560-bp open reading frame encoding 520 amino acid residues. The coding region has 84% similarity to the human GALNS cDNA at amino acid level. The mouse Galns gene was mapped by interspecific backcross analysis to the distal region of chromosome 8 where it co-segregates with Aprt. Northern blot analysis showed a wide expression of a single-copy gene, being higher especially in liver and kidney. The Galns gene was isolated from S129vJ genomic library and its genomic organization was characterized. The mouse Galns gene was about 50-kb long and organized into 14 exons and 13 introns. All intron-exon splice junctions conformed to the GT/AG consensus sequence except exon 8/intron 8 junction. Primer extension shows multiple transcription initiation sites between -44 and -75 although major transcription initiation site was observed at -90 bp from the ATG codon. The 5'-flanking region lacks canonical TATA and CAAT box sequences, but is G+C rich with 10 GC boxes (potential Sp1 binding sites), characteristic of a housekeeping gene promoter.
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PMID:The mouse N-acetylgalactosamine-6-sulfate sulfatase (Galns) gene: cDNA isolation, genomic characterization, chromosomal assignment and analysis of the 5'-flanking region. 1069 74

Mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA) is a rare, autosomal recessive disorder with a prevalence of 1 in 170,000 live births. It is caused by a deficiency of N-acetylgalactosamine 6-sulfatase (GALNS), a lysosomal hydrolase encoded by a gene on human chromosome 16q24.3. Mucopolysaccharidosis type IVA is the only known MPS that is associated with structural defects in dental enamel. GALNS cleaves the sulfate group from N-acetylgalactosamine 6-sulfate and galactose 6-sulfate, which are specifically found in keratan sulfate and chondroitin 6-sulfate. A pathologic absence of GALNS activity results in the accumulation of these glycosaminoaglycans in the urine and in the lysosomes of tissues that turn them over. There is currently no animal model for MPS IVA. To learn more about how a GALNS deficit could lead to enamel defects, we have cloned and characterized a full-length pig GALNS cDNA. GALNS mRNA was localized in developing teeth by in situ hybridization, Northern blot, and reverse-transcription polymerase chain reaction analyses, while GALNS substrates were localized using immunohistochemistry. We report that secretory ameloblasts were positive for GALNS mRNA, as well as for keratan sulfate and chondroitin 6-sulfate. We conclude that enamel defects associated with the loss of GALNS activity in persons with MPS IVA are likely to result from the pathological accumulation of keratan sulfate and chondroitin 6-sulfate in the lysosomes of secretory stage ameloblasts.
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PMID:Porcine N-acetylgalactosamine 6-sulfatase (GALNS) cDNA sequence and expression in developing teeth. 1248 54

Mucopolysaccharidosis type IVA (MPS IVA; OMIM #253000) or Morquio A syndrome is an autosomal recessive inborn error resulting from the deficient activity of the lysosomal enzyme, N-acetylgalactosamine-6-sulfatase (GALNS), and the progressive lysosomal accumulation of sulfated glycosaminoglycans. Clinically, the severe form of this lysosomal storage disease is characterized by a characteristic severe bone dysplasia and normal intelligence. To date, a variety of mutations have been associated with the severe MPS IVA phenotype. Here, we report the GALNS mutations in six severe MPS IVA patients from four unrelated Tunisian families. For mutation detection, each of the 14 exons and adjacent intron-exon junctions of the GALNS gene were sequenced after PCR-amplification from genomic DNA. Two novel mutations were identified: a G to A transition in the conserved 5' donor splice site of intron 1 (GACgt-->GACat: designated IVS1(+1g-->a)) and a G to C transversion in codon 66 of exon 2 predicting a glycine to arginine substitution (G66R). The IVS1(+1g-->a) mutation was homozygous in five similarly affected patients from three presumably unrelated families, but haplotype analysis suggested a common ancestor. The affected patient in the fourth family was homozygous for the G66R mutation. These are the first GALNS mutations causing severe MPS IVA disease identified in Tunisia. These molecular findings provide genotype/phenotype correlations, and permit accurate carrier detection, prenatal diagnosis, and counseling for MPS IVA disease in Tunisia where first cousin consanguineous mating remains frequent.
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PMID:Mucopolysaccharidosis type IV: N-acetylgalactosamine-6-sulfatase mutations in Tunisian patients. 1637 44

Mucopolysaccharidosis type IV A (MPS IV A) is an autosomal recessive disorder resulting from the deficient activity of the lysosomal enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS) and the progressive lysosomal accumulation of keratane sulfate. Clinically, the MPS IV A differs from the other MPS by the localisation of the keratane sulfate in skelet and in eyes associated to the conservation of a normal intelligence. To date, the characterization and purification of the GALNS gene made a research for pathogenic mutations in patients with MPS IV A easier. These mutations are responsible of severe, intermediate or mild phenotype. The aim for this work was the research of clinical, biologic and molecular characteristics of two Tunisian MPS IV A patients who were offsprings of consanguineous mating. Enzymatic and urinary diagnostics suggested a MPS IV A phenotype. A novel homozygous mutation IVS1+1G-A was identified by direct sequencing in the GALNS gene of the two patients. Identification of GALNS mutations provide genotype/phenotype correlations and permit the precision of anomalies responsible of Morquio A phenotype in concerned families.
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PMID:[Clinical, biologic and molecular characteristics of two Tunisian MPS IV A patients]. 1726 40

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and transmitted as an autosomal recessive trait. This is the first systematic mutation screen in Chinese MPS IVA patients. Mutation detections in 24 unrelated Chinese MPS IVA patients were performed by PCR and direct sequencing of exons or the mRNA of GALNS. A total of 42 mutant alleles were identified, belonging to 27 different mutations. Out of the 27 mutations, 16 were novel, including 2 splicing mutations (c.567-1G>T and c.634-1G>A), 2 nonsense mutations (p.W325X and p.Q422X) and 12 missense mutations (p.T88I, p.H142R, p.P163H, p.G168L, p.H236D, p.N289S, p.T312A, p.G316V, p.A324E, p.L366P, p.Q422K and p.F452L). p.G340D was found to be a common mutation in the Chinese MPS IVA patients, accounting for 16.7% of the total number of mutant alleles. The results show that the mutations in Chinese MPS IVA patients are also family specific but have a different mutation spectrum as compared to those of other populations.
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PMID:Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations. 2057 28


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