1. FUT6 deficiency compromises basophil function by selectively abrogating their sialyl-Lewis x expression
- Author
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Puan, K., San Luis, B., Yusof, N., Kumar, D., Andiappan, A., Lee, W., Cajic, S., Vuckovic, D., Chan, J., Döllner, T., Hou, H., Jiang, Y., Tian, C., Agee, M., Aslibekyan, S., Auton, A., Babalola, E., Bell, R., Bielenberg, J., Bryc, K., Bullis, E., Cameron, B., Coker, D., Partida, G., Dhamija, D., Das, S., Elson, S., Filshtein, T., Fletez-Brant, K., Fontanillas, P., Freyman, W., Gandhi, P., Heilbron, K., Hicks, B., Hinds, D., Huber, K., Jewett, E., Kleinman, A., Kukar, K., Lane, V., Lin, K., Lowe, M., Luff, M., McCreight, J., McIntyre, M., McManus, K., Micheletti, S., Moreno, M., Mountain, J., Mozaffari, S., Nandakumar, P., Noblin, E., O’Connell, J., Petrakovitz, A., Poznik, G., Schumacher, M., Shastri, A., Shelton, J., Shi, J., Shringarpure, S., Tran, V., Tung, J., Wang, X., Wang, W., Weldon, C., Wilton, P., Rapp, E., Poidinger, M., Wang, D., Soranzo, N., Lee, B., Rötzschke, O., Puan, Kia Joo [0000-0003-2445-3154], Kumar, Dilip [0000-0002-1848-3034], Andiappan, Anand Kumar [0000-0002-8442-1544], Cajic, Samanta [0000-0001-5820-0732], Chan, Jing De [0000-0002-2249-5273], Hou, Han Wei [0000-0001-6631-6321], Rapp, Erdmann [0000-0001-6618-2626], Poidinger, Michael [0000-0002-1047-2277], Soranzo, Nicole [0000-0003-1095-3852], Rötzschke, Olaf [0000-0001-8336-5248], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), and School of Mechanical and Aerospace Engineering
- Subjects
0301 basic medicine ,Fucosyltransferase ,Allergy ,QH301-705.5 ,Population ,Medicine (miscellaneous) ,T-Cells ,Genetic predisposition to disease ,Gene Expression ,Basophil ,Immunoglobulin E ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,Leukocyte Count ,0302 clinical medicine ,Sequence Homology, Nucleic Acid ,medicine ,Humans ,Medicine [Science] ,Leukocyte Rolling ,Biology (General) ,education ,Sialyl Lewis X Antigen ,Cells, Cultured ,education.field_of_study ,biology ,Base Sequence ,Gene Expression Profiling ,Mast-Cells ,Eosinophil ,Mast cell ,Fucosyltransferases ,Molecular biology ,Null allele ,Basophils ,030104 developmental biology ,medicine.anatomical_structure ,Sialyl-Lewis X ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Mechanical engineering [Engineering] ,General Agricultural and Biological Sciences ,E-Selectin - Abstract
Sialyl-Lewis x (sLex, CD15s) is a tetra-saccharide on the surface of leukocytes required for E-selectin-mediated rolling, a prerequisite for leukocytes to migrate out of the blood vessels. Here we show using flow cytometry that sLex expression on basophils and mast cell progenitors depends on fucosyltransferase 6 (FUT6). Using genetic association data analysis and qPCR, the cell type-specific defect was associated with single nucleotide polymorphisms (SNPs) in the FUT6 gene region (tagged by rs17855739 and rs778798), affecting coding sequence and/or expression level of the mRNA. Heterozygous individuals with one functional FUT6 gene harbor a mixed population of sLex+ and sLex- basophils, a phenomenon caused by random monoallelic expression (RME). Microfluidic assay demonstrated FUT6-deficient basophils rolling on E-selectin is severely impaired. FUT6 null alleles carriers exhibit elevated blood basophil counts and a reduced itch sensitivity against insect bites. FUT6-deficiency thus dampens the basophil-mediated allergic response in the periphery, evident also in lower IgE titers and reduced eosinophil counts., Puan and San Luis et al. find that FUT6, encoding a fucosyltransferase, is required for the “rolling” behavior of certain white blood cells that enables them to move from blood vessels to tissues. They show that FUT6 deficiency leads to a loss of the tetrasaccharide sLex on the surface of basophils, resulting in cells that are less sticky and therefore less able to form the necessary adhesions for exiting the blood vessel to drive the allergic reaction.
- Published
- 2021