Decreased availability of GDP-l-fucose in a patient with LAD II with normal GDP-d-mannose dehydratase and FX protein activities

Körner, Christian; Linnebank, Michael; Koch, Hans Georg; Harms, Erik; Figura, Kurt Von; Marquardt, Thorsten

doi:10.1002/jlb.66.1.95

Cited by 25 publications

(20 citation statements)

References 13 publications

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“…Indeed, although the main clinical symptoms that identify LAD II syndrome are similar in the Arab and Turkish patients, some differences in the clinical phenotype were observed (1,2,5,19). Importantly, activity of GMD was reduced in cell lysates from Arab patients (18), whereas it was normal in the Turkish patient (21). Taken together, these data would be consistent with different molecular defects in the Turkish and Arab patients.…”

Section: Discussionsupporting

confidence: 54%

“…The activity of GMD was not altered in the Turkish patient (21). The Arab LAD II patients and the Turkish child responded differently to replacement therapy with oral fucose: thus, whereas a significant response was observed in the Turkish patient, both as expression of selectin ligands and as improvement of the clinical symptoms (22), no effects were observed in the two Arab children even after long-term administration of high doses of fucose (5).…”

mentioning

confidence: 99%

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Impairment of the Golgi GDP-l-Fucose Transport and Unresponsiveness to Fucose Replacement Therapy in LAD II Patients

et al. 2001

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

Impairment of the Golgi GDP-l-Fucose Transport and Unresponsiveness to Fucose Replacement Therapy in LAD II Patients

et al. 2001

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“…In LAD II the conversion of GDP-mannose to GDP-fucose is impaired due to the inactivity of GDP-D-mannose-4,6-dehydratase (16). Since the activity of GDP-D-mannose-4,6-dehydratase was normal in fibroblasts from our patient (17), the hypofucosylation must result from a different defect. Here we report that the hypofucosylation results from a severely decreased import of GDP-fucose into the Golgi.…”

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confidence: 72%

A New Type of Carbohydrate-deficient Glycoprotein Syndrome Due to a Decreased Import of GDP-fucose into the Golgi

Lübke¹,

Figura²,

Körner³

et al. 1999

Journal of Biological Chemistry

127

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The fucosylation of glycoproteins was found to be deficient in a patient with a clinical phenotype resembling that of leukocyte adhesion deficiency type II (LAD II). While in LAD II hypofucosylation of glycoconjugates is secondary to an impaired synthesis of GDP-fucose due to a deficiency of the GDP-D-mannose-4,6-dehydratase, synthesis of GDP-fucose was normal in our patient (Kö rner, C., Linnebank, M., Koch, H., Harms, E., von Figura, K., and Marquardt, T. (1999) J. Leukoc. Biol., in press). Import of GDP-fucose into Golgi-enriched vesicles was composed of a saturable, high affinity and a nonsaturable component. In our patient the saturable high affinity import of GDP-fucose was deficient, while import of UDP-galactose and the activity of GDPase, which generates the nucleoside phosphate required for antiport of GDP-fucose, were normal. Addition of L-fucose to the medium of fibroblasts restored the fucosylation of glycoproteins. We propose that this new form of carbohydrate-deficient glycoprotein syndrome is caused by impaired import of GDP-fucose into the Golgi.

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“…17 Cell extracts of our patient displayed normal activity levels of the dehydratase and the FX protein. 18 Instead, decreased import of GDP-fucose into the Golgi of these cells was observed, indicating that the basis for LADII might be a defect in the transport rather than the synthesis of GDP-fucose. 19 …”

Section: Effects Of Fucose In Ladii Are Reversible 331mentioning

confidence: 92%

Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts

Lühn

Marquardt

Harms

et al. 2001

Blood

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Leukocyte adhesion deficiency type II (LADII) is a rare inherited disorder of fucose metabolism. Patients with LADII lack fucosylated glycoconjugates, including the carbohydrate ligands of the selectins, leading to an immunodeficiency caused by the lack of selectin-mediated leukocyte-endothelial interactions. A simple and effective therapy has recently been described for LADII, based on the administration of oral fucose. Parallel to this treatment the lack of E-and Pselectin ligands on neutrophils was corrected, and high peripheral neutrophil counts were reduced to normal levels. This study reports that discontinuation of this therapy leads to the complete loss of E-selectin ligands within 3 days and of P-selectin ligands within 7 days. Peripheral neutrophil counts increased parallel to the decrease of selectin ligands. Selectin ligands reappeared promptly after resumption of the fucose therapy, demonstrating a causal relationship between fucose treatment and selectin ligand expression and peripheral neutrophil counts. ( IntroductionSelectins initiate the contact formation between leukocytes and endothelial cells and thereby the extravasation of leukocytes. 1 They form a family of 3 cell adhesion molecules of which 2 are inducible on the surface of endothelial cells (E-and P-selectin), and one is constitutively expressed on most leukocytes (L-selectin). Although the precise carbohydrate structure of selectin ligands has not yet been determined definitively, ample evidence suggests that they resemble or are derivatives of the tetrasaccharide sialyl Lewis X (sLe x ) (NeuAc␣2,3-Gal␤1,4[Fuc␣1,3] GlcNAc). Fucose is an essential structural element of all known selectin ligands as has been demonstrated in mice deficient for the gene for fucosyltransferase VII. 2 Thus, a defect in fucose metabolism would be expected to severely hamper leukocyte entry into tissue.Leukocyte adhesion deficiency type II (LADII) is a still-undefined genetic defect that results in the lack of fucosylated glycoconjugates, including sialyl Lewis X. Patients suffer from recurrent episodes of infections, persistent leukocytosis, and severe mental and growth retardation. [3][4][5] Leukocyte rolling in postcapillary venules of such patients is markedly reduced, and selectin ligands on leukocytes are missing. 6,7 The genetic defect seems to affect intracellular GDPfucose supply because culturing of fibroblasts of different LADII patients in the presence of fucose can rescue the expression of fucosylated glycoconjugates. 8,9 We have recently described a new case of LADII 10 and have established a successful therapy based on the administration of oral fucose. 9 Since the onset of therapy, neutrophil counts were reduced to normal levels, no episodes of fever were observed, and nearly normal expression levels of first Pand later of E-selectin ligands were reached while fucose doses were gradually increased. However, we could not demonstrate whether fucose treatment did indeed cause the changes or whether they merely occurred coincidentally. This questi...

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Decreased availability of GDP-l-fucose in a patient with LAD II with normal GDP-d-mannose dehydratase and FX protein activities

Cited by 25 publications

References 13 publications

Impairment of the Golgi GDP-l-Fucose Transport and Unresponsiveness to Fucose Replacement Therapy in LAD II Patients

Impairment of the Golgi GDP-l-Fucose Transport and Unresponsiveness to Fucose Replacement Therapy in LAD II Patients

A New Type of Carbohydrate-deficient Glycoprotein Syndrome Due to a Decreased Import of GDP-fucose into the Golgi

Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts

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