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J M Aerts

Publications and source records attributed to J M Aerts.

At least 37 records · Page 2Linked to original sources
PubMed1998

The human chitotriosidase gene. Nature of inherited enzyme deficiency.

The human chitinase, named chitotriosidase, is a member of family 18 of glycosylhydrolases. Following the cloning of the chitotriosidase cDNA (Boot, R. G., Renkema, G. H., Strijland, A., van Zonneveld, A. J., and Aerts, J. M. F. G. (1995) J. Biol. Chem. 270, 26252-26256), the gene and mRNA have been investigated. The chitotriosidase gene is assigned to chromosome 1q31-q32. The gene consists of 12 exons and spans about 20 kilobases. The nature of the common deficiency in chitotriosidase activity is reported. A 24-base pair duplication in exon 10 results in activation of a cryptic 3' splice site, generating a mRNA with an in-frame deletion of 87 nucleotides. All chitotriosidase-deficient individuals tested were homozygous for the duplication. The observed carrier frequency of about 35% indicates that the duplication is the predominant cause of chitotriosidase deficiency. The presence of the duplication in individuals from various ethnic groups suggests that this mutation is relatively old.

Amino Acid Sequence↗
PubMed1998

Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages.

In various mammals, enzymatically active and inactive members of family 18 glycosyl hydrolases, containing chitinases, have been identified. In man, chitotriosidase is the functional chitinolytic enzyme, whilst the homologous human cartilage 39-kDa glycoprotein (HC gp-39) does not exhibit chitinase activity and its function is unknown. This study establishes that HC gp-39 is a chitin-specific lectin. It is experimentally demonstrated that a single amino acid substitution in the catalytic centre of the 39-kDa isoform of chitotriosidase, which generates a similar sequence to that in HC gp-39, results in a loss of hydrolytic activity and creates the capacity to bind to chitin. The possible implication of the finding for chitinolytic and chitin-binding proteins that are produced in high quantities by activated macrophages are discussed.

Adipokines↗
PubMed1998

Oligosaccharide excretion in adult Gaucher disease.

Gaucher disease is a lysosomal storage disease characterized by storage of glucocerebroside due to lysosomal glucocerebrosidase deficiency. Increased urinary excretion of sialyloligosaccharides and mannosylglycoasparagines has been described for two patients with the infantile form of the disease, probably as a consequence of obstruction of lysosomal functioning due to the glycolipid accumulation in lysosomes. By thin-layer chromatography, we found increased urinary oligosaccharide excretion in a series of adult non-neuronopathic patients. Oligosaccharide patterns were comparable between patients and also with the pattern observed in infantile Gaucher disease. Composition was analysed by methanolysis and gas chromatography. Mannose and N-acetylglucosamine are the main carbohydrates in all oligosaccharide bands. A statistically significant correlation was found between oligosaccharide excretion and the severity of the disease expressed as severity score index. Patients treated with enzyme replacement therapy showed a reduction up to 65% of the original oligosaccharide excretion after 1 year of treatment, comparable with the reduction in spleen volume.

Adult↗
PubMed1998

Energy and protein metabolism between 3 and 6 weeks of age of male broiler chickens selected for growth rate or for improved food efficiency.

1. A new open-circuit respiration unit consisting of 6 respiration chambers, gas analysis unit and data-acquisition system is briefly described. 2. Energy and protein metabolism in broiler lines selected for improved food efficiency (FC) or for growth rate (GL) were measured weekly from 3 to 6 weeks of age. 3. Gross and apparent metabolisable energy intake per kg W0.75 was on average higher for GL than for FC chickens without differences in metabolisability. Fed and fasted heat production per kg W0.75 did not differ between the lines. FC chickens retained less energy per kg W0.75 than GL chickens. 4. FC chickens deposited much less of the retained energy as fat than their GL counterparts and also showed greater protein conversion efficiency. The leaner composition of the body weight gain in FC chickens was confirmed by the estimated lower fat deposition per kg W0.75 and by the lower fat: protein ratio.

Aging↗
PubMed1997

Synthesis, sorting, and processing into distinct isoforms of human macrophage chitotriosidase.

Chitotriosidase, the human analogue of chitinases from non-vertebrate species, has recently been identified. The macrophage-derived enzyme is remarkably heterogeneous in molecular mass and isoelectric point. The synthesis and modification of the enzyme in cultured macrophages is reported. Chitotriosidase is synthesized as a 50-kDa protein with a pI of about 6.5 and 7.2. It is predominantly secreted, but in part processed into a 39-kDa form with a pI of 8.0 that accumulates in lysosomes. In the C-terminal extension of the 50-kDa chitotriosidase, sialic-acid containing O-linked glycans are present, causing its heterogeneous acidic isoelectric point. Chitotriosidase lacks N-linked glycans and the mechanism of routing to lysosomes proves to be distinct from that of soluble, N-glycosylated, lysosomal enzymes. It was observed that, in macrophages, alternative splicing generates a distinct chitotriosidase mRNA species, encoding a 40-kDa chitotriosidase that is C-terminally truncated. This enzyme is almost identical to the 39-kDa chitotriosidase formed from the 50-kDa precursor by proteolytic processing. It is concluded that the C-terminus present in the 50-kDa chitotriosidase, but absent in the 39-kDa isoform, was found to mediate tight binding to chitin. In the blood stream the secretory 50-kDa chitotriosidase occurs predominantly, whilst in tissues the 39-kDa form is also abundant. These findings are consistent with the data on the synthesis and processing of chitotriosidase in the cultured macrophage model.

Animals↗
PubMed1997

Glucocerebrosidase genotype of Gaucher patients in The Netherlands: limitations in prognostic value.

Gaucher disease is a recessively inherited lysosomal storage disorder that is caused by a deficiency in glucocerebrosidase activity. The clinical expression is markedly heterogeneous with respect to age of onset, progression, severity, and neurological involvement. The relative incidence of glucocerebrosidase (GC) mutations has been studied extensively for Jewish but not for non-Jewish Caucasian patient populations. The present survey on mutant GC genotypes prevalent in Gaucher disease in The Netherlands was taken of 72 patients from different genetic backgrounds. This number is more than half the total number of affected Gaucher patients to be expected on the basis of the incidence of the disorder in this country. Analysis of nine GC mutations led to the identification of 74% of the mutant GC alleles in patients from 44 unrelated Dutch families (i.e., families that have lived in The Netherlands for at least several generations) and of 44% of the mutant GC alleles in patients from nine unrelated families that recently immigrated from both European and non-European countries. The N370S (cDNA 1226G) GC mutation proved to occur most frequently (41%) in the unrelated Dutch patients and less frequently (6%) in the unrelated immigrant patients and was always associated with the nonneuronopathic (Type 1) form of the disease. Apart from the association of the N370S mutation with Type 1 Gaucher disease, the prognostic value of GC genotyping was limited, since a particular GC genotype did not correlate closely to a specific clinical course, or to a specific relative responsiveness to enzyme-supplementation therapy.

Blotting, Southern↗
PubMed1997

Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease.

We prospectively evaluated the clinical and biochemical responses to enzyme-replacement therapy (ERT) with macrophage-targeted glucocerebrosidase (Ceredase) infusions in 5 patients (age, 3.5-8.5 years) with type 3 Gaucher's disease. The patients were followed for up to 5 years. Enzyme dosage ranged from 120 to 480 U/kg of body weight/month. Systemic manifestations of the disease regressed in all patients. Neurological deficits remained stable in 3 patients and slightly improved in 1. One patient developed myoclonic encephalopathy. Cognitive deterioration occurred in 1 patient and electroencephalographic deterioration in 2. Sequential cerebrospinal fluid (CSF) samples were obtained during the first 3 years of treatment in 3 patients and were analyzed for biochemical markers of disease burden. Glucocerebroside and psychosine levels were not elevated in these specimens, whereas chitotriosidase and quinolinic acid were elevated in 2 patients. Progressive decrease in the CSF levels of these latter macrophage markers during 3 years of treatment implies a decreased number of Gaucher cells in the cerebral perivascular space. Similar changes were not observed in the patient who had a poor neurological outcome. In conclusion, ERT reverses systemic manifestations of type 3 Gaucher's disease and appears to reduce the burden of Gaucher cells in the brain-CSF compartment in some patients.

Antibodies↗
PubMed1997

Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease.

In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFalpha, M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNFalpha were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.

Adolescent↗
PubMed1997

Differential effects of enzyme supplementation therapy on manifestations of type 1 Gaucher disease.

BACKGROUND: In type 1 Gaucher disease (GD), the accumulation of glucocerebroside in macrophages, caused by deficient activity of glucocerebrosidase, results in a variety of disease manifestations. In addition to the characteristic features of hepatosplenomegaly, cytopenia, and bone abnormalities, resting energy expenditure (REE) and glucose production are increased. In this study the effects of enzyme supplementation therapy on metabolic parameters in relation to other disease manifestations in type 1 GD patients are investigated. PATIENTS AND METHODS: In 12 adult type 1 GD patients, measurements of REE (by indirect calorimetry), liver and spleen volume (by spiral computerized axial tomography [CT]) and hemoglobin and platelet count were obtained before and after 6 months of alglucerase therapy (15 U/kg per month). In 7 of the 12 patients hepatic glucose production was measured by infusing 3-3H glucose. For comparison, REE and glucose metabolism were studied in 7 weight- and age-matched healthy subjects. RESULTS: REE and glucose production were increased in GD patients as compared with controls (REE: 29.8 kcal/kg/24 h +/- 3.6 and 23.1 +/- 2.3 kcal/kg/24 h, respectively, P < 0.05; glucose production: 14.00 mumol/kg/min +/- 0.51 and 10.77 mumol/kg/min +/- 0.26, respectively, P < 0.03). There were no differences in plasma glucose concentrations. Whereas the elevated REE decreased after 6 months of alglucerase therapy from 129% to 120% of predicted values (P < 0.01), the increase in hepatic glucose production did not change. An increase in weight occurred after 6 months of treatment (1.7 +/- 0.8 kg, P < 0.001), which was accounted for by an increase in fat mass of 1.6 +/- 1.5 kg (P < 0.02). Hemoglobin levels increased from 11.2 mg/dL to 12.1 mg/dL (P = 0.05) and platelet counts rose from 84 x 10(9)/L to 113 x 10(9)/L (P < 0.05). Although liver and spleen volumes decreased by approximately 10% and approximately 20%, respectively, there was no correlation between the decrease in organ volumes and the decrease in REE. CONCLUSIONS: Treatment with alglucerase improves hypermetabolism and organomegaly in GD, whereas the increase in glucose production persists. Therefore, the dose-response effects of alglucerase are variable for the different manifestations of type 1 GD.

Adult↗
PubMed1997

Plasma and metabolic abnormalities in Gaucher's disease.

An overview of the most important plasma abnormalities that can be found in Gaucher's disease is presented in this chapter. Attention is focussed on their practical applications and possible clinical relevance. In addition, the result of studies on metabolic alterations in Gaucher's disease are reviewed.

Gaucher Disease↗
PubMed1997

Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy.

In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown. We performed a detailed study of parameters of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients (14 splenectomized) before and after treatment with enzyme supplementation therapy. Pre-treatment aPTT and PT were prolonged in 42% and 38% of patients, respectively. In 30-60% serious deficiencies (< 50%) of coagulation factors XI, XII, VII, X, V and II were observed. The low levels of factor V correlated with platelet count and were inversely associated with splenic volume. Levels of inhibitors were mildly decreased. Markers for activation of coagulation (thrombin-antithrombin (TAT) complex) and fibrinolysis (PAP complex, fibrin cleavage product D-dimer) were significantly elevated, especially in the splenectomized patients, indicating ongoing activation of these processes. After 12 months of enzyme supplementation therapy partial correction occurred. Thus, severe disorders of the coagulation system occur in Gaucher disease, contributing to the bleeding tendency. The deficiencies may be the result of consumption of coagulation factors caused by ongoing low-level coagulation activation. possibly due to mononuclear cell activation.

Adult↗
PubMed1997

Image analysis to measure activity index of animals.

The objective of the study was to present a method to quantify the behavioural response of animals to their micro-environment by using a camera system and a digitiser board. An algorithm was developed for analysing images and calculating activity, occupied zone and boundary of the animals. The developed method was tested on 3 different applications and animals. In the first application, the behavioural responses of broiler chickens to their thermal environment was measured. In the second application behavioural responses of pigs to their thermal environment were measured. In the third application, the response of water fleas to a chromium pollution was measured using the developed technique. Based on the experimental results, it can be concluded that the developed image analysis technique can be employed to quantify the behavioural responses of the tested animals to their micro-environment, in an easy and accurate way.

Adaptation, Physiological↗
PubMed1996

Plasma tumor necrosis factor-a (TNF-a) levels in Gaucher disease.

Tumor necrosis factor-a (TNF-a) levels were measured in the plasma of patients with different types of Gaucher disease (GD) and patients with other lysosomal storage diseases. The highest TNF-a levels were observed in the most severe neuronopathic type of GD, exceeding those found in healthy individuals as well as patients with other lysosomal disorders. Type I GD cases showed a wide range of TNF-a levels ranging from normal to 2.5 x the highest control value. TNF-a is a pleiotropic cytokine produced mainly by activated macrophages. Our data suggest that it may play a role in the pathophysiology of GD disease.

Gaucher Disease↗
PubMed1996

The enzymatic hydrolysis of 6-acylamino-4-methylumbelliferyl-beta-D-glucosides: identification of a novel human acid beta-glucosidase.

Fluorogenic 6-acylamino-4-methylumbelliferyl-beta-D-glucosides were found to be poor substrates for the three known human beta-glucosidases, i.e., lysosomal and non-lysosomal glucocerebrosidases and cytosolic broad-specificity beta-glucosidase. However, homogenates of human tissues and human cell types showed significant enzymatic hydrolysis of 6-ethanoylamino-4-methylumbelliferyl-beta-D-glucoside (EMGlc) due to the activity of a hitherto undescribed beta-glucosidase, called here EMGlc-ase. It was shown that the isozyme is hardly active towards 4-methylumbelliferyl-beta-D-glucoside or glucosylceramide. EMGlc-ase exhibits maximal activity at pH 4.5 and 5.0 in the absence and presence of sodium taurocholate respectively. It is a soluble lysosomal enzyme with a discrete isoelectric point of about 5.0. EMGlc-ase is not inhibited by conduritol B-epoxide, is activated by sodium taurocholate and binds strongly to Concanavalin A. This enzyme is not deficient in relation to Gaucher disease.

Animals↗
PubMed1996

Quantitative analysis of the targeting of mannose-terminal glucocerebrosidase. Predominant uptake by liver endothelial cells.

Gaucher's disease is an inherited lysosomal storage disorder that is caused by a deficiency of glucocerebrosidase. The resulting accumulation of the substrate glucosylceramide in macrophages of liver, spleen, and bone marrow causes severe clinical symptoms. Gaucher's disease is treated by intravenous administration of a modified glucocerebrosidase (Alglucerase), which has exposed mannose residues to promote uptake by target macrophages. To evaluate the effectiveness of the targeting of Alglucerase, we studied the fate of the enzyme in the rat. Intravenously injected Alglucerase was rapidly cleared from the circulation (half-life 2.0 +/- 0.5 min). The liver was the main site of uptake, with 65.6 +/- 1.2% of the dose present at 10 min after injection. Smaller amounts ( < 3% of the dose) were taken up by spleen and bone marrow. Previous injection with mannan substantially increased the plasma half-life of the enzyme (14.8 +/- 3.2 min versus 1.7 +/- 0.3 min in solvent-preinjected controls) and uptake of the enzyme by liver, spleen and bone marrow was reduced by > 90%. These findings indicate that the enzyme is taken up by these organs via mannose-specific receptors. Subcellular fractionation of the liver indicated that the enzyme is internalized and transported to the lysosomes. By isolating various liver cell types after injection of the Alglucerase, it was found that endothelial cells are the main site of uptake of the enzyme: 60.8 +/- 3.4% of the total liver uptake. Parenchymal and Kupffer cells were responsible for 31.0 +/- 3.1% and 8.2 +/- 0.7% of the hepatic uptake, respectively. We conclude that Alglucerase is rapidly cleared from the circulation by mannose-specific receptors in liver, spleen, and bone marrow. However, less than 10% of the enzyme taken up by the liver is accounted for by Kupffer cells, the hepatic target cells for therapeutic intervention. It is suggested that alterations of the formulation of the therapeutic enzyme may lead to a higher uptake by Kupffer cells and other macrophages, and thus to a more (cost)effective therapy of Gaucher's disease.

Animals↗