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:3.1.6.4 (chondroitinase)
2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is an autosomal-recessive disorder caused by a deficiency of lysosomal N-acetylgalactosamine-6-sulfate sulfatase (GALNS; E.C.3.1.6.4). GALNS is required to degrade glycosaminoglycans, keratan sulfate (KS), and chondroitin-6-sulfate. Accumulation of undegraded substrates in lysosomes of the affected tissues leads to a systemic bone dysplasia. We summarize information on 148 unique mutations determined to date in the GALNS gene, including 26 novel mutations (19 missense, four small deletions, one splice-site, and two insertions). This heterogeneity in GALNS gene mutations accounts for an extensive clinical variability within MPS IVA. Seven polymorphisms that cause an amino acid change, and nine silent variants in the coding region are also described. Of the analyzed mutant alleles, missense mutations accounted for 78.4%; small deletions, 9.2%; nonsense mutation, 5.0%; large deletion, 2.4%; and insertions, 1.6%. Transitional mutations at CpG dinucleotides accounted for 26.4% of all the described mutations. The importance of the relationship between methylation status and distribution of transitional mutations at CpG sites at the GALNS gene locus was elucidated. The three most frequent mutations (over 5% of all mutations) were represented by missense mutations (p.R386C, p.G301C, and p.I113F). A genotype/phenotype correlation was defined in some mutations. Missense mutations associated with a certain phenotype were studied for their effects on enzyme activity and stability, the levels of blood and urine KS, the location of mutations with regard to the tertiary structure, and the loci of the altered amino acid residues among sulfatase proteins.
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PMID:Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). 1628 98

Design of efficient treatment strategies for diseases requires clarification of the nature of each mutation causing the disease. In this study, we have investigated three factors to correctly predict the correlation between genotype and phenotype on N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene responsible for one of lysosomal storage diseases, known as mucopolysaccharidosis IVA (MPS IVA); (i) evolutionary conservation of amino acid residues among family proteins, (ii) conservativeness of amino acid changes in GALNS, and (iii) structural conservation of amino acid residue. The results showed that (i) the likelihood of a missense variant causing MPS IVA was directly correlated with the level of evolutionary conservation and inversely correlated with conservativeness but not correlated with the structural conservation, (ii) the disease-causative mutations were 9 times more likely to be located on the 'highly conserved' residues than the polymorphisms, (iii) the likelihood of 'non-conservative' amino acid changes in missense mutations was 6.8 times higher than those in the polymorphisms, (iv) the degree of evolutionary conservation was nearly as predictive in phenotype as that of conservativeness of amino acid changes, and (v) the combination of the two factors, evolutionary conservation and conservativeness, provides a better association between missense variants and clinical severity with higher sensitivity (83.5-88.9%) and specificity (71.4-88.3%), than that obtained by either factor alone. These findings suggest that the combination of evolutionary conservation and conservativeness is a useful tool to predict the effect of each mutation on the clinical phenotype and can be applied to the analysis of phenotype/genotype relation in other genetic diseases.
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PMID:Determinant factors of spectrum of missense variants in mucopolysaccharidosis IVA gene. 1683 23

Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is an autosomal recessive lysosomal storage disorder caused by a genetic deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS; E.C.3.1.6.4). GALNS is required to degrade keratan sulfate (KS) and chondroitine-6-sulfate (C6S). The accumulation of undegraded substrates in lysosomes of the affected tissues leads to a systemic bone dysplasia. Total urine glycosaminoglycans (GAG) in patients with MPS IVA are close to the normal range so it is difficult to distinguish this disease based on urine GAG excretion. Another potential disease marker could be KS levels in urine and plasma. Although the enzymatic diagnosis of affected patients with MPS IVA can be made, the detection of obligate heterozygotes by enzymatic measurement is less reliable because of a marked overlap of GALNS in fibroblasts or leucocytes from affected phenotype and normal controls. The genetic heterozygoty of MPS IVA has been facilitated by the isolation and characterization of the full lengh cDNA encoding human GALNS. Conventional therapy is symptomatic and limited to palliative procedures, which have virtually no impact upon mortality. To date, there is still no general consensus about the effectiveness of bone marrow transplantation. In the future, gene therapy could represent a great therapeutic improvement.
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PMID:[Mucopolysaccharidosis IVA (Morquio A syndrome): clinical, biological and therapeutic aspects]. 1726 33

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The aims of this study were to establish Chinese hamster ovary (CHO) cells overexpressing recombinant human GALNS (rhGALNS) and to assess pharmacokinetics and tissue distribution of purified enzymes by using MPS IVA knock-out mouse (Galns(-/-)). The CHO-cell derived rhGALNS was purified from the media by a two-step affinity chromatography procedure. The rhGALNS was administered intravenously to 3-month-old Galns(-/-) mice at a single dose of 250U/g of body weight. The treated mice were examined by assaying the GALNS activity at baseline and up to 240min to assess clearance of the enzyme from blood circulation. The mice were sacrificed 4h after infusion of the enzyme to study the enzyme distribution in tissues. The rhGALNS was purified 1317-fold with 71% yield. The enzyme was taken up by Galns(-/-) chondrocytes (150U/mg/15h). The uptake was inhibited by mannose-6-phosphate. The enzyme activity disappeared from circulation with a half-life of 2.9min. After enzyme infusion, the enzyme was taken up and detected in multiple tissues (40.7% of total infused enzymes in liver). Twenty-four hours after a single infusion of the fluorescence-labeled enzymes into MPS IVA mice, biodistribution pattern showed the amount of tagged enzyme retained in bone, bone marrow, liver, spleen, kidney, and heart. In conclusion, we have shown that the phosphorylated rhGALNS is delivered to multiple tissues, including bone, and that it functions bioactively in Galns(-/-) chondrocytes implying a potential enzyme replacement treatment.
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PMID:Characterization and pharmacokinetic study of recombinant human N-acetylgalactosamine-6-sulfate sulfatase. 1733 63

Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The natural history of this disease is incompletely understood. To study which variables influence the clinical outcome, we conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints. A total of 326 patients (172 male, 154 female) from 42 countries enrolled in the Morquio A Registry programme. The mean age of patients enrolled was 14.9 years for males and 19.1 years for females, with a wide range of 1-73 years. Sixty-four per cent of the patients were under 18 years. Initial symptoms were recognized between 1 and 3 years of age (mean age 2.1 years) and mean age at diagnosis for the patients was 4.7 years. A progressive skeletal dysplasia was commonly observed among the MPS IVA patients. Fifty per cent of patients underwent surgical operations to improve their quality of life. The most frequent surgical sites include neck (51%), ear (33%), leg (26%) and hip (25%). The birth length for affected males and females was 52.2 +/- 4.7 cm and 52.2 +/- 4.5 cm, respectively. The final adult height for affected males and females was 122.5 +/- 22.5 cm and 116.5 +/- 20.5 cm, respectively. The results of this study provide a reference for assessment of efficacy for studies of novel therapies.
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PMID:International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. 1734 14

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), required for degradation of keratan sulfate and chondroitin-6-sulfate. In order to study the effects of a missense mutation in the active site cysteine in the GALNS gene that is conserved in all mammalian sulfatases, we produced a p.C76S (an active site replacement) knock-in mouse by replacing the Cys76 with Ser in the endogenous murine Galns by targeted mutagenesis. Homozygous Galns(tm(C76S)slu) mice had no detectable GALNS enzyme activity. At age of 2-4 months, lysosomal storage was present primarily within reticuloendothelial cells such as Kupffer cells and spleen sinusoidal lining cells. Vacuolar change was present in glomerular visceral epithelial cells and was not present in hepatocytes or renal tubular cells. In the brain, hippocampal and neocortical neurons and meningeal cells showed lysosomal storage. Radiographs revealed no change in the skeletal bones of mice up to 12 months old. Thus, the Galns(tm(C76S)slu) mice had visceral storage of GAGs in organs but lacked the skeletal features of human MPS IVA. In contrast to a previously reported transgenic model (Galns(tm(hC79S.mC76S)slu)), in which the inactive human GALNS transgene was overexpressed, no reduction in other sulfatases was observed. In addition, the Galns(tm(C76S)slu) mice displayed milder storage. We conclude that the milder phenotype is characteristic of isolated GALNS deficiency while the more severe phenotype reflected in the Galns(tm(hC79S.mC76S)slu) mice was due to deficiency of other sulfatases caused by oversaturation of the sulfate modifying enzyme by the inactive human gene product.
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PMID:Murine model (Galns(tm(C76S)slu)) of MPS IVA with missense mutation at the active site cysteine conserved among sulfatase proteins. 1749 92

Mucopolysaccharidosis IVA is an autosomal recessive disease caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS gene was performed for seven MPS IVA patients with attenuated phenotypes from three unrelated families. Four of 5 missense mutations identified in this study (p.F167V, p.R253W, p.R380S, p.P484S) and two reported (p.F97V, p.N204K), associated with attenuated phenotypes, were characterized using in vitro stable expression experiments, enzyme kinetic study, protein processing and structural analysis. The stably expressed mutant enzymes defining the attenuated phenotype exhibited a considerable residual activity (1.2-36.7% of the wild-type GALNS activity) except for p.R380S. Enzyme kinetic studies showed that p.F97V, p.F167V and p.N204K have lower affinity to the substrate compared with other mutants. The p.F97V enzyme was the most thermolabile at 55 degrees C. Immunoblot analyses indicated a rapid degradation and/or an insufficiency in processing in the mutant proteins. Tertiary structure analysis revealed that although there was a tendency for 'attenuated' mutant residues to be located on the surface of GALNS, they have a different effect on the protein including modification of the hydrophobic core and salt-bridge formation and different potential energy. This study demonstrates that 'attenuated' mutant enzymes are heterogeneous in molecular phenotypes, including biochemical properties and tertiary structure.
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PMID:Effect of 'attenuated' mutations in mucopolysaccharidosis IVA on molecular phenotypes of N-acetylgalactosamine-6-sulfate sulfatase. 1787 18

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to accumulation of keratan sulfate (KS) and chrondroitin-6-sulfate. The pharmacokinetics and biodistributions were determined for two recombinant human GALNSs produced in CHO cell lines: native GALNS and sulfatase-modifier-factor 1 (SUMF1) modified GALNS. Preclinical studies of enzyme replacement therapy (ERT) by using two GALNS enzymes were performed on MPS IVA mice. The half-lives in blood circulation of two phosphorylated GALNS enzymes were similar (native, 2.4 min; SUMF1, 3.3 min). After intravenous doses of 250 units/g body weight were administered, each enzyme was primarily recovered in liver and spleen, with detectable activity in other tissues including bone and bone marrow. At 4 h post-injection, enzyme activity was retained in the liver, spleen, bone and bone marrow at levels that were 20-850% of enzyme activity in the wild-type mice. After intravenous doses of 250 units/g of native GALNS, and 250, 600 or 1000 units/g of SUMF1-GALNS were administered weekly for 12 weeks, MPS IVA mice showed marked reduction of storage in visceral organs, sinus lining cells in bone marrow, heart valves, ligaments and connective tissues. A dose-dependent clearance of storage material was observed in brain. The blood KS level assayed by tandem mass spectrometry was reduced nearly to normal level. These preclinical studies demonstrate the clearance of tissue and blood KS by administered GALNS, providing the in vivo rationale for the design of ERT trials in MPS IVA.
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PMID:Enzyme replacement therapy in a murine model of Morquio A syndrome. 1805 56

To study the quantitative relationship between the mutant N-acetylgalactosamine-6-sulfatase and the occurrence of mucopolysaccharidosis IVA, the human N-acetylgalactosamine-6-sulfatase with 117 mutations was quantified using the amino-acid distribution probability, then the mutations and clinical outcomes were coupled using the cross-impact analysis. The results show that a patient has 0.94 chance of being mucopolysaccharidosis IVA when a new mutation occurs in N-acetylgalactosamine-6-sulfatase.
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PMID:Descriptively quantitative relationship between mutated N-acetylgalactosamine-6-sulfatase and mucopolysaccharidosis IVA. 1937 25

Mucopolysaccharidosis IVA (MPS IVA, Morquio A disease) is an inherited lysosomal storage disorder that features skeletal chondrodysplasia caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Human GALNS was bioengineered with the N-terminus extended by the hexaglutamate sequence (E6) to improve targeting to bone (E6-GALNS). We initially assessed blood clearance and tissue distribution. Next, to assess the effectiveness of storage clearance and reversal of pathological phenotype, a dose of 250 U/g of enzyme was given weekly to Morquio A mice (adults: 12 or 24 weeks, newborn: 8 weeks). Sulfatase modifier factor 1 (SUMF1) was co-transfected to activate the enzyme fully. The E6-GALNS tagged enzyme had markedly prolonged clearance from circulation, giving over 20 times exposure time in blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with residual enzyme activity demonstrable at 48 hours after infusion. The pathological findings in adult mice treated with tagged enzyme showed substantial clearance of the storage materials in bone, bone marrow, and heart valves, especially after 24 weekly infusions. Mice treated from the newborn period showed marked reduction of storage materials in tissues investigated. These findings indicate the feasibility of using tagged enzyme to enhance delivery and pathological effectiveness in Morquio A mice.
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PMID:Enhancement of drug delivery: enzyme-replacement therapy for murine Morquio A syndrome. 2033 69


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