Campus ICO-Germans Trias i Pujol
Office: (+34) 93 557 2800 extn 4050
Laboratory: (+34) 93 557 2800 extn 4051
Josep Carreras Leukaemia Research Institute
IJC Building
Can Ruti Campus
Ctra de Can Ruti
Camí de les Escoles s/n
08916 Badalona
Barcelona
Spain
Laboratory 1-23 Office 1-27 (first floor)
DirectionsSummary
Blood group ABO system consists of A and B oligosaccharide antigens and the antibodies against those antigens (anti-A and anti-B antibodies, respectively). Matching of ABO blood groups is fundamental for safe blood transfusion. Because A and B antigens may also be expressed on other types of cells than red blood cells, the ABO matching is also important in the transplantation of cells/tissues/organs. Starting from the cloning of the human blood group ABO genes and the elucidation of the allelic basis of the ABO system, we have been investigating ABO genes, the gene-encoded A and B glycosyltransferases, and A and B oligosaccharide antigens, their enzymatic reaction products. We have contributed to science and medicine in a variety of research fields such as molecular genetics, human genetics, population genetics, genotyping, enzymology, biochemistry, glycobiology, hematology, immunology, cellular and developmental biology, forensic science, cancer research, and even in the study of evolution.
Research
We have the following lines of research in progress or under development.
- ABO polymorphism alters the susceptibility to cardiovascular diseases (venous thromboembolism, coronary artery disease, coagulation disease), infectious diseases (brain malaria caused byPlasmodium falciparum, stomach ulcer by Helicobacter pylori, viral gastroenteritis by Noroviruses), and cancer (pancreatic and gastric cancers).
We are interested in the molecular mechanisms conferring this differential disease susceptibility.
- The ABO family of genes (ABO, GBGT1, A3GALT2, GGTA1, and GLT6D1) has evolved through gene duplications followed by divergence. In addition to the acquisition of different enzymatic activity and specificity by the gene-encoded glycosyltransferases, the genes may have suffered translocation, recombination, and additional genetic/epigenetic changes.
We would like to delineate the processes that might have occurred during the evolution of the ABO family of genes.
- Cell-surface glycosylation patterns, also known as glycoprofiles, change during proliferation and differentiation of cells, including the hematopoietic stem cells, which produce a variety of cell types present in blood and lymph. The glycoprofile is radically altered after cells are transformed to become cancerous. Being exposed on cell surface and occasionally excreted into blood and lymph, cancer-specific glycoepitopes can serve as the targets of medical intervention as well as the markers for non-invasive diagnosis and monitoring of cancer.
We anticipate that cells exhibiting different glycoprofiles may possess differential susceptibility to certain chemotherapeutic drugs. We will FACS sort leukemic cell line cells/clinical specimens of leukemic cells into populations exhibiting different glycoprofiles, and examine their drug sensitivity. Because several stem-cell markers are already known to be glycoepitopes, this may allow the identification of medications that are specific to cancer cells with stem cell properties.
- Our research group has recently developed a method to customize cells exhibiting certain glycolipids by the introduction of retroviral vectors to express a selected set of glycosyltransferases into cells having only the core structure of glycolipid.
We have been utilizing this method to create cells with cancer-specific glycoepitopes, which will soon be used to screen a human single chain (scFv) antibody library and to identify monoclonal single chain antibodies that are reactive to the selected cancer-specific glycoepitopes. Those antibodies may have a potential to be modified to molecularly target leukemic cells for immunotherapy such as adoptive transfer of T cells expressing chimeric antigen receptor against those epitopes.
For more information on the molecular genetic basis of the ABO blood group system, please see the following pages.
English site (http://sites.google.com/site/abobloodgroup/)
Catalan site (https://sites.google.com/site/grupsanguiniaboab0/)
Spanish site (http://sites.google.com/site/gruposanguineoab0/home)
Japanese site (http://sites.google.com/site/abobloodgroup/home2)
Awards
- Docteur honoris causa de Republique francaise (Dr. h.c) from L’Universite de Toulouse III (Universite Paul Sabatier), France (2011)
- Wako Lecture, Japanese Society of Blood Transfusion & Cell Therapy, (co-organized with the ISBT (2009).
- Chaire d’Excellence, Pierre de Fermat Honorary Lecture at the Pierre de Fermat Symposium on Molecular Genetic Bases of Blood Group Genes (2009)
- State of the Art Lecture at the ISBT meeting (2000)
- Keynote Lecture at the Annual Meeting of the Japanese Society of Blood Transfusion (1994)
- The Jean Julliard Prize from the International Society of Blood Transfusion (1992)
Collaborations
Professor Naruya Saitou, National Institute of Genetics, Mishima, Japan
Professor Antoine Blancher, Faculté de Médecine Purpan, Université Paul Sabatier, (Université de Toulouse III), Toulouse, France
Professor Jaume Bertranpetit, IBE - Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
Selected publications
Yamamoto M, Cid E, Yamamoto F
ABO blood group A transferases catalyze the biosynthesis of FORS blood group FORS1 antigen upon deletion of exon 3 or 4.
Blood Adv 26 Dec 2017, 1 (27) 2756-2766. Epub 20 Dec 2017Evolutionarily related ABO and GBGT1 genes encode, respectively, A and B glycosyltransferases (AT and BT) and Forssman glycolipid synthase (FS), which catalyze the biosynthesis of A and B, and Forssman (FORS1) oligosaccharide antigens responsible for the ABO and FORS blood group systems. Humans are a Forssman antigen-negative species; however, rare individuals with Apae phenotype express FORS1 on their red blood cells. We previously demonstrated that the replacement of the LeuGlyGly tripeptide sequence at codons 266 to 268 of human AT with GBGT1-encoded FS-specific GlyGlyAla enabled the enzyme to produce FORS1 antigen, although the FS activity was weak. We searched for additional molecular mechanisms that might allow human AT to express FORS1. A variety of derivative expression constructs of human AT were prepared. DNA was transfected into COS1 (B3GALNT1) cells, and cell-surface expression of FORS1 was immunologically monitored. To our surprise, the deletion of exon 3 or 4, but not of exon 2 or 5, of human AT transcripts bestowed moderate FS activity, indicating that the A allele is inherently capable of producing a protein with FS activity. Because RNA splicing is frequently altered in cancer, this mechanism may explain, at least partially, the appearance of FORS1 in human cancer. Furthermore, strong FS activity was attained, in addition to AT and BT activities, by cointroducing 1 of those deletions and the GlyGlyAla substitution, possibly by the synergistic effects of altered intra-Golgi localization/conformation by the former and modified enzyme specificity by the latter.
More informationYamamoto F
Evolutionary divergence of the ABO and GBGT1 genes specifying the ABO and FORS blood group systems through chromosomal rearrangements.
Sci Rep 24 Aug 2017, 7 (1) 9375. Epub 24 Aug 2017Human alleles at the ABO and GBGT1 genetic loci specify glycosylation polymorphism of ABO and FORS blood group systems, respectively, and their allelic basis has been elucidated. These genes are also present in other species, but presence/absence, as well as functionality/non-functionality are species-dependent. Molecular mechanisms and forces that created this species divergence were unknown. Utilizing genomic information available from GenBank and Ensembl databases, gene order maps were constructed of a chromosomal region surrounding the ABO and GBGT1 genes from a variety of vertebrate species. Both similarities and differences were observed in their chromosomal organization. Interestingly, the ABO and GBGT1 genes were found located at the boundaries of chromosomal fragments that seem to have been inverted/translocated during species evolution. Genetic alterations, such as deletions and duplications, are prevalent at the ends of rearranged chromosomal fragments, which may partially explain the species-dependent divergence of those clinically important glycosyltransferase genes.
More informationCid E, Yamamoto M, Yamamoto F
Non-AUG start codons responsible for ABO weak blood group alleles on initiation mutant backgrounds.
Sci Rep 31 Jan 2017, 7 41720. Epub 31 Jan 2017Histo-blood group ABO gene polymorphism is crucial in transfusion medicine. We studied the activity and subcellular distribution of ABO gene-encoded A glycosyltransferases with N-terminal truncation. We hypothesized that truncated enzymes starting at internal methionines drove the synthesis of oligosaccharide A antigen in those already described alleles that lack a proper translation initiation codon. Not only we tested the functionality of the mutant transferases by expressing them and assessing their capacity to drive the appearance of A antigen on the cell surface, but we also analyzed their subcellullar localization, which has not been described before. The results highlight the importance of the transmembrane domain because proteins deprived of it are not able to localize properly and deliver substantial amounts of antigen on the cell surface. Truncated proteins with their first amino acid well within the luminal domain are not properly localized and lose their enzymatic activity. Most importantly, we demonstrated that other codons than AUG might be used to start the protein synthesis rather than internal methionines in translation-initiation mutants, explaining the molecular mechanism by which transferases lacking a classical start codon are able to synthesize A/B antigens.
More informationYamamoto M, Cid E, Yamamoto F
Crosstalk between ABO and Forssman (FORS) blood group systems: FORS1 antigen synthesis by ABO gene-encoded glycosyltransferases.
Sci Rep 30 Jan 2017, 7 41632. Epub 30 Jan 2017A and B alleles at the ABO genetic locus specify A and B glycosyltransferases that catalyze the biosynthesis of A and B oligosaccharide antigens, respectively, of blood group ABO system which is important in transfusion and transplantation medicine. GBGT1 gene encodes Forssman glycolipid synthase (FS), another glycosyltransferase that produces Forssman antigen (FORS1). Humans are considered to be Forssman antigen-negative species without functional FS. However, rare individuals exhibiting Apae phenotype carry a dominant active GBGT1 gene and express Forssman antigen on RBCs. Accordingly, FORS system was recognized as the 31st blood group system. Mouse ABO gene encodes a cis-AB transferase capable of producing both A and B antigens. This murine enzyme contains the same GlyGlyAla tripeptide sequence as FSs at the position important for the determination of sugar specificity. We, therefore, transfected the expression construct into appropriate recipient cells and examined whether mouse cis-AB transferase may also exhibit FS activity. The result was positive, confirming the crosstalk between the ABO and FORS systems. Further experiments have revealed that the introduction of this tripeptide sequence to human A transferase conferred some, although weak, FS activity, suggesting that it is also involved in the recognition/binding of acceptor substrates, in addition to donor nucleotide-sugars.
More informationYamamoto F, Clausen H, White T, Marken J, Hakomori S
Molecular genetic basis of the histo-blood group ABO system.
Nature 17 May 1990, 345 (6272) 229-33. The histo-blood group ABO, the major human alloantigen system, involves three carbohydrate antigens (ABH). A, B and AB individuals express glycosyltransferase activities converting the H antigen into A or B antigens, whereas O(H) individuals lack such activity. Here we present a molecular basis for the ABO genotypes. The A and B genes differ in a few single-base substitutions, changing four amino-acid residues that may cause differences in A and B transferase specificity. A critical single-base deletion was found in the O gene, which results in an entirely different, inactive protein incapable of modifying the H antigen.
More information
