FUT6 deficiency compromises basophil function by selectively abrogating their sialyl-Lewis x expression

  • Commun Biol. 2021 Jul 2;4(1):832. doi: 10.1038/s42003-021-02295-8.
Kia Joo Puan  #  1  2 ,  Boris San Luis  #  1 ,  Nurhashikin Yusof  1 ,  Dilip Kumar  1 ,  Anand Kumar Andiappan  1 ,  Wendy Lee  1 ,  Samanta Cajic  3 ,  Dragana Vuckovic  4 ,  Jing De Chan  1 ,  Tobias Döllner  1 ,  Han Wei Hou  5  6 ,  Yunxuan Jiang  7 ,  Chao Tian  7 ,  23andMe Research Team ,  Erdmann Rapp  3  8 ,  Michael Poidinger  1 ,  De Yun Wang  9 ,  Nicole Soranzo  4 ,  Bernett Lee  1 ,  Olaf Rötzschke  10
Affiliations
  • 1. Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
  • 2. Shanghai Junshi Biosciences Co., Ltd, Shanghai, China.
  • 3. Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
  • 4. Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
  • 5. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 6. School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore.
  • 7. 23andMe, Inc., Sunnyvale, CA, USA.
  • 8. glyXera GmbH, Magdeburg, Germany.
  • 9. Department of Otolaryngology, National University of Singapore, Singapore, Singapore.
  • 10. Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. [email protected].
  • # Contributed equally.
PMID: 34215830 DOI: 10.1038/s42003-021-02295-8
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.

Products