Glucocerebrosidase genotype of Gaucher patients in The Netherlands: Limitations in prognostic value

Boot, Rolf G.; Hollak, Carla E. M.; Verhoek, Marri; Sloof, Paul; Poorthuis, Ben J. H. M.; Kleijer, Wim J.; Wevers, Ron A.; Oers, Marinus H. J. van; Mannens, Marcel M.A.M.; Aerts, Johannes M. F. G.; Weely, Sonja van

doi:10.1002/(sici)1098-1004(1997)10:5<348::aid-humu3>3.0.co;2-b

Cited by 37 publications

(24 citation statements)

References 39 publications

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“…In the interest of obtaining a homogenous sample for crystallography, the single glycosylation site (Asn 35 ) was mutated (N35Q). YKL-39 N35Q protein crystals in complex with chitohexaose (GlcNAc) 6 were obtained through co-crystallization of 30 mg/ml protein with 1 mM (GlcNAc) 6 in conditions containing 23 % PEG 3000 and 0.1 M sodium citrate (pH 6). Crystals were cryoprotected in 30 % ethylene glycol, 23 % PEG 3000 and 0.1 M sodium citrate (pH 6), cryocooled and diffraction data were collected at the ESRF BM14 (European Synchrotron Radiation Facility Bending Magnet beamline 14).…”

Section: Structure Solutionmentioning

confidence: 99%

“…The final enzyme concentrations were 2 nM for hCHT and 20 nM for YKL-39. The Table 1 Details of data collection and structure refinement for YKL-39 in complex with (GlcNAc) 6 Values in parentheses are for the highest resolution shell. R merge , R work and R free were calculated according to the standard equations: R merge = i |I i − <I |/ i I i , where I i and <I> are the observed intensity and the average intensity of multiple observations of symmetry identical reflections respectively; R work = F obs | − |F calc / |F obs |, where F obs and F calc are the observed and calculated structure factors respectively; and R free was computed as in R work , but only for (2 %) randomly selected reflections, which were omitted from refinement.…”

Section: Chitinase Activity Assaymentioning

confidence: 99%

“…The screen revealed several potential binding partners for YKL-39 ( Figure 1A). A common characteristic of these glycan ligands was the presence of β (1,4) glycosidic bonds, and the strongest binders were the chitooligosaccharides (GlcNAc) 5 and (GlcNAc) 6 . To quantify the strength of this interaction, intrinsic tryptophan fluorescence was used, exploiting the presence of several conserved tryptophan residues ( Figure 1B), which have been shown to play a role in substrate binding by family 18 chitinase [31,43,44].…”

Section: Ykl-39 Selectively Binds Chitooligosaccharides With Micromolmentioning

confidence: 99%

“…Indeed, dose-dependent changes in intrinsic tryptophan fluorescence were observed in the presence of chitooligosaccharides ( Figure 1C). This allowed determination of the dissociation constants for these ligands, indicating that YKL-39 has a higher affinity for (GlcNAc) 6 (K d = 0.6 + − 0.1 μM) than for the shorter ligand (GlcNAc) 3 (32 + − 4 μM).…”

Section: Ykl-39 Selectively Binds Chitooligosaccharides With Micromolmentioning

confidence: 99%

“…The C-terminal domain of the 39 kDa isoform has been shown to be involved in the binding of chitin [3], whereas the 50 kDa form is secreted from macrophages and the truncated form is not. Rather, it is routed to the lysosomes and can be used as a marker for measuring the progression of Gaucher's disease [4][5][6]. AMCase has a similar domain structure, but a distinct expression pattern, being expressed in the gastrointestinal tract and lung by tissue macrophages and endothelial cells [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties

Schimpl

Rush

Betou

et al. 2012

Biochemical Journal

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The chitinase-like proteins YKL-39 (chitinase 3-like-2) and YKL-40 (chitinase 3-like-1) are highly expressed in a number of human cells independent of their origin (mesenchymal, epithelial or haemapoietic). Elevated serum levels of YKL-40 have been associated with a negative outcome in a number of diseases ranging from cancer to inflammation and asthma. YKL-39 expression has been associated with osteoarthritis. However, despite the reported association with disease, the physiological or pathological role of these proteins is still very poorly understood. Although YKL-39 is homologous to the two family 18 chitinases in the human genome, it has been reported to lack any chitinase activity. In the present study, we show that human YKL-39 possesses a chitinase-like fold, but lacks key active-site residues required for catalysis. A glycan screen identified oligomers of N-acetylglucosamine as preferred binding partners. YKL-39 binds chitooligosaccharides and a newly synthesized derivative of the bisdionin chitinase-inhibitor class with micromolar affinity, through a number of conserved tryptophan residues. Strikingly, the chitinase activity of YKL-39 was recovered by reverting two non-conservative substitutions in the active site to those found in the active enzymes, suggesting that YKL-39 is a pseudo-chitinase with retention of chitinase-like ligand-binding properties.

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Section: Structure Solutionmentioning

confidence: 99%

Section: Chitinase Activity Assaymentioning

confidence: 99%

Section: Ykl-39 Selectively Binds Chitooligosaccharides With Micromolmentioning

confidence: 99%

Section: Ykl-39 Selectively Binds Chitooligosaccharides With Micromolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties

Schimpl

Rush

Betou

et al. 2012

Biochemical Journal

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Glucocerebrosidase mutations among African-American patients with type 1 Gaucher disease

et al. 2001

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While the inherited deficiency of the enzyme glucocerebrosidase (Gaucher disease) is panethnic in its distribution, there have not been studies of the mutations encountered in specific ethnic groups in the United States, other than those on Ashkenazi Jews. We present the clinical descriptions and genotypes of seven patients of African-American ancestry with type 1 Gaucher disease, and summarize the published literature regarding the genotypes encountered in this population. All seven of the patients had moderate-to-severe manifestations of the disease, and all developed symptoms by adolescence. Genotypic analyses revealed that no two probands shared the same genotype. The common mutations N370S, c.84-85insG, IVS2+1 G-->A, and R463C were not seen. Mutation L444P was present on one allele in each of the patients; but the same mutation was encountered as a single point mutation in three of the patients, and as part of a recombinant allele in four of the patients. Southern blot analyses revealed a glucocerebrosidase fusion allele in one patient, and a duplication resulting from recombination in the region downstream from the glucocerebrosidase gene in three of the patients. Five different point mutations (A90T, R48W, N117D, R170C, and V352L), one deletion mutation (c.222-224 delTAC), and one insertion mutation (c.153-154 insTACAGC) were encountered. Our results demonstrate that there is significant genotypic heterogeneity among African-American patients with type 1 Gaucher disease, and that recombinations in the glucocerebrosidase gene locus are particularly common in this patient group. Published 2001 Wiley-Liss, Inc.

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Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients

et al. 2002

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Gaucher disease (GD), the most prevalent lysosomal storage disease characterized by a remarkable degree of clinical variability, results from deleterious mutations in the glucocerebrosidase gene (GBA). In this paper we report the molecular characterization of 144 unrelated Italian GD patients with the three types of the disease. The allelic frequencies of Italians are reported and the mutation profile is analyzed. Besides the common N370S, L444P, RecNciI, G202R, IVS2+1G>A, D409H, F213I mutations, the different molecular strategies, used for the mutation detection, identified the rare N107L, R131C, R170C, R170P, N188S, S196P, R285C, R285H, W312C, D399N, A446P, IVS10-1G>A, Rec∆55, total gene deletion, as well as 12 mutant alleles that were exclusively present in the Italian population until now: the previously reported R353G, N370S+S488P mosaicism, IVS8(-11delC)-14T>A), Rec I, Y418C, and the seven novel alleles D127X, P159T, V214X, T231R, L354X, H451R, and G202R+M361I. The wide phenotypic differences observed within the genotypic groups as well as between siblings implicate a significant contribution of other modifying genetic and/or non-genetic factors and claim a comprehensive valuation of the patient including clinical., biochemical and molecular investigations for prognosis, appropriate interventive therapy and reliable genetic counseling.

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Glucocerebrosidase genotype of Gaucher patients in The Netherlands: Limitations in prognostic value

Cited by 37 publications

References 39 publications

Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties

Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties

Glucocerebrosidase mutations among African-American patients with type 1 Gaucher disease

Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients

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