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Identification of a Missense Mutation (G329A; Arg110→ Gln) in the Human FUT7 Gene
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Institute of Laboratory Medicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Institute of Laboratory Medicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
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2001 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 34, 31575-31582 p.Article in journal (Refereed) Published
Abstract [en]

The human FUT7 gene codes for the α1,3-fucosyltransferase VII (Fuc-TVII), which is involved in the biosynthesis of the sialyl Lewis x (SLex) epitope on human leukocytes. The FUT7 gene has so far been considered to be monomorphic. Neutrophils isolated from patients with ulcerative colitis were examined for apparent alterations in protein glycosylation patterns by Western blot analysis using monoclonal antibodies directed against SLex and SLex-related epitopes. One individual showed lower levels of SLex expression and an elevated expression of CD65s compared to controls. The coding regions of the FUT7 gene from this individual were cloned, and a G329A point mutation (Arg110 → Gln) was found in one allele, whereas the other FUT7 allele was wild type. No Fuc-TVII enzyme activity was detected in COS-7 cells transiently transfected with the mutated FUT7 construct. TheFUT7 Arg110 is conserved in all previously cloned vertebrate α1,3-fucosyltransferases. Polymerase chain reaction followed by restriction enzyme cleavage was used to screen 364 unselected Caucasians for the G329A mutation, and a frequency of ≤1% for this mutation was found (3 heterozygotes). Genetic characterization of the family members of one of the additional heterozygotes identified one individual carrying the G329A mutation in both FUT7alleles. Peripheral blood neutrophils of this homozygously mutated individual showed a lowered expression of SLex and an elevated expression of CD65s when analyzed by Western blot and flow cytometry. The homozygous individual was diagnosed with ulcer disease, non-insulin-dependent diabetes, osteoporosis, spondyloarthrosis, and Sjögren's syndrome but had no history of recurrent bacterial infections or leukocytosis.

Place, publisher, year, edition, pages
2001. Vol. 276, no 34, 31575-31582 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-47286DOI: 10.1074/jbc.M104165200OAI: oai:DiVA.org:liu-47286DiVA: diva2:268182
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Carbohydrate dependent adhesion of leukocytes and the role of fucosyltransferase VII
Open this publication in new window or tab >>Carbohydrate dependent adhesion of leukocytes and the role of fucosyltransferase VII
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Galectins, E-and P-selectins are carbohydrate-binding proteins that are up regulated at inflammatory lesions. Selectins expressed ou the activated endothelium mediate transient binding to leukocyte ligands that require sequential action of α 2,3-sialyltransferases and a 1,3-fucosyltransferases. ln leukocytes α1,3 fucosyltransferase VII adds fucose to α 2,3- sialylated lactosarnine acceptors in the final step of the biosynthesis of the selectin binding epitope sialyl Lewis x.

The finding of low sialyl Lewis x expression in polymorphonuclear leukocytes from a patient with ulcerative colitis led to the discovery of a missense mutation (G329A) in the human gene coding for α1,3 fucosyltransferase VII, FUT7. Studies including enzymatic and immunochemical analysis oftransfected cell lines and isolated polymorphonuclear leukocytes from patients confirmed that this mutation impair the ability of α1,3 fucosyltransferase VII to synthesize sialyl Lewis x. The frequency of the mutation were measured in a mixed Swedish population and found to be -1 %. One individual carrying the FUT7-G329A mutation homozygously was identified. This individual suffered from ulcer disease, noninsulin-dependent diabetes, osteoporosis, spondyloarthrosis, and Sjögren's syndrome, but the relationship between disease and the mutation is not established.

Studies using an in vitro flow chamber assay showed that transfected B-lymphoma cells and Epstein-Barr virus transformed B cells only transcribing FUT7-G329A were not able to interact with E-selectin during flow whereas polymorphonuclear leukocytes from the FUT7-G329A homozygous individual interacted well with both P- and E selectin during flow. The mRNA level of the fucosyltransferase IV coding gene, FUT4, was found to be elevated in the homozygous individual, which resulted in elevated levels ofthe CD65s epitope. However, transfected B-lymphoma cells and Epstein- Barr virus transformed cells did not show a similar elevation of FUT4 mRNA. In in vitro studies galectin-1 and- 3 were observed to be able to recruit polymorphonuclear leukocytes during flow. This thesis gives further insight into the molecular mechanisms leading to carbohydrate dependent dynamic adhesion between polymorphonuclear leukocytes and lectins during inflammation.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 41 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 762
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25551 (URN)9999 (Local ID)91-7373-204-4 (ISBN)9999 (Archive number)9999 (OAI)
Public defence
2003-03-28, Berzeliussalen, Universitetssjukhuset, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-09-24Bibliographically approved

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Bengtson, PerLundblad, ArnePåhlsson, Peter

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